恢復動脈粥樣硬化(atherosclerosis)之動脈的血流的動脈血管重建的方法，包括球囊血管成形術、支架置入術和冠狀動脈旁路等。然而動脈發生再狹窄是這些重建方法上的一個主要限制因素。其中以球囊血管成形術所造成的血管成形術後再狹窄主要是由新生內膜的形成和縮窄再塑造所導致。新內膜的形成是由於血管受損後造成中膜收縮表現型態喪失，最後導致血管平滑肌細胞（vascular smooth muscle cells, VSMCs）的遷移和增生。Dihydroaustrasulfone alcohol是合成台灣軟珊瑚Cladiella australis海洋天然物austrasulfone的先驅物。Dihydroaustrasulfone alcohol具有抗發炎、神經保護、抗腫瘤和抗動脈粥樣硬化的活性。雖然dihydroaustrasulfone alcohol已被證明可以抑制血管新內膜形成，但其對於血管平滑肌細胞的作用機轉尚未闡明。因此，本論文的目的是來探討dihydroaustrasulfone alcohol是否對於血管平滑肌細胞增生具有抑制作用及研究其機轉。Dihydroaustrasulfone alcohol顯著地抑制人類主動脈平滑肌細胞(human aortic smooth muscle cells, HASMCs)增生、DNA合成及遷移，但不誘導細胞死亡。Dihydroaustrasulfone alcohol也抑制血小板衍生性生長因子(platelet-derived growth factor, PDGF) 所誘發細胞週期蛋白依賴性激酶 (cyclin-dependent kinases, CDK)2 (CDK2)、CDK4、細胞週期蛋白(cyclin) D1 (cyclin D1) 和cyclin E 的表現。另外，dihydroaustrasulfone alcohol抑制血小板衍生性生長因子所誘發細胞外信號調控激酶(extracellular signal-regulated kinase, ERK)1/2 (ERK1/2)的磷酸化，而其對於磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase, PI3K)/(Akt)的磷酸化並沒有影響。此外，使用PD98059 (高度選擇性之ERK抑制劑)來治療，可阻斷血小板衍生性生長因子所誘發cyclin D1和cyclin E的表現量上昇及血小板衍生性生長因子所誘發p27kip1的表現量下降。此外，dihydroaustrasulfone alcohol也能抑制血小板衍生性生長因子所誘發血管平滑肌細胞合成表現型態的形成。在動物實驗方面，dihydroaustrasulfone alcohol降低了在大白鼠頸動脈氣球擴張術所引起血管損傷再狹窄的平滑肌細胞增生。在免疫化染色實驗結果顯示，dihydroaustrasulfone alcohol明顯減少增生細胞核抗原（proliferating cell nuclear antigen, PCNA）的表現量，及改變血管平滑肌細胞的表現型態從合成表現型態到收縮表現型態。我們的發現提供了dihydroaustrasulfone alcohol可以成為血管保護作用見解機轉之重要的洞察力，它可能對於血管閉塞性疾病是一種有用的治療劑。總之，以影響細胞週期之相關蛋白質及抑制平滑肌細胞增生，達到減緩動脈粥樣硬化與血管再狹窄之進展。

Arterial reconstruction procedures, including balloon angioplasty, stenting and coronary artery bypass, are used to restore blood flow in atherosclerotic arteries. Restenosis of these arteries is a major limitation of the application of these procedures. Post-angioplasty restenosis results from two major processes: neointimal formation and constrictive remodelling. Neointimal formation is initiated by arterial injury with a resultant loss of contractile phenotype in tunica media, leading to vascular smooth muscle cells (VSMCs) migration and proliferation. Dihydroaustrasulfone alcohol is the synthetic precursor of austrasulfone, which is a marine natural product, isolated from the Taiwanese soft coral Cladiella australis. Dihydroaustrasulfone alcohol has anti-inflammatory, neuroprotective, antitumor and anti-atherogenic properties. Although dihydroaustrasulfone alcohol has been shown to inhibit neointima formation, its effect on human VSMCs has not been elucidated. We examined the effects and the mechanisms of action of dihydroaustrasulfone alcohol on proliferation, migration and phenotypic modulation of human aortic smooth muscle cells (HASMCs). Dihydroaustrasulfone alcohol significantly inhibited proliferation, DNA synthesis and migration of HASMCs, without inducing cell death. Dihydroaustrasulfone alcohol also inhibited platelet-derived growth factor (PDGF)-induced expression of cyclin-dependent kinases (CDK) 2, CDK4, cyclin D1 and cyclin E. In addition, dihydroaustrasulfone alcohol inhibited PDGF-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whereas it had no effect on the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/(Akt). Moreover, treatment with PD98059, a highly selective ERK inhibitor, blocked PDGF-induced upregulation of cyclin D1 and cyclin E and downregulation of p27kip1. Furthermore, dihydroaustrasulfone alcohol also inhibits VSMC synthetic phenotype formation induced by PDGF. For in vivo studies, dihydroaustrasulfone alcohol decreased smooth muscle cell proliferation in a rat model of restenosis induced by balloon injury. Immunohistochemical staining showed that dihydroaustrasulfone alcohol noticeably decreased the expression of proliferating cell nuclear antigen (PCNA) and altered VSMC phenotype from a synthetic to contractile state. Our findings provide important insights into the mechanisms underlying the vasoprotective actions of dihydroaustrasulfone alcohol and suggest that it may be a useful therapeutic agent for the treatment of vascular occlusive disease.

誌謝…………………………………………………………………………… i
中文摘要……………………………………………………………………… ii
英文摘要………………………………………………………………………iv
目錄……………………………………………………………………………vi
圖次……………………………………………………………………………viii
第一章 緒論……………………………………………………………… 1
第一節 動脈粥樣硬化的簡介及病理過程……………………………… 1
第二節 血管平滑肌細胞與動脈硬化及血管再狹窄之關係…………… 6
第三節 血小板衍生性生長因子(PDGF)與血管平滑肌細胞之關係…… 11
第四節 細胞週期及其調控細胞週期…………………………………… 21
第五節 由MAPK路徑所調控之細胞週期的關係………………………… 27
第六節 由PI3K/Akt路徑所調控之細胞週期的關係…………………… 33
第七節 海洋化合物之藥理性質與應用………………………………… 38
第二章 研究動機與目的…………………………………………………… 43
第三章 材料與方法……………………………………………………… 45
第一節 實驗用藥………………………………………………………… 45
第二節 人類主動脈平滑肌細胞培養…………………………………… 45
第三節 人類主動脈平滑肌細胞處理…………………………………… 45
第四節 細胞增生測試-Bromodeoxyuridine (BrdU) Incorporation Assay. 46
第五節 細胞週期變化之分析…………………………………………… 46
第六節 細胞存活率分析………………………………………………… 47
第七節 細胞遷移測試（Cell Migration Assay）……………………… 48
第八節 細胞核及細胞質蛋白質萃取…………………………………… 50
第九節 西方墨點轉漬分析法…………………………………………… 50
第十節 大白鼠頸動脈氣球擴張術損傷的動物模式…………………… 53
第十一節 統計分析……………………………………………………… 55
第四章 實驗結果…………………………………………………………… 56
第五章 討論……………………………………………………………… 73
第六章 結論……………………………………………………………… 82
第七章 參考文獻………………………………………………………… 84
第八章 附錄………………………………………………………………… 124

1. Chen K, Lindsey JB, Khera A, De Lemos JA, Ayers CR, Goyal A, Vega GL, Murphy SA, Grundy SM, McGuire DK: Independent associations between metabolic syndrome, diabetes mellitus and atherosclerosis: observations from the Dallas Heart Study. Diabetes & Vascular Disease Research 2008, 5(2):96-101.
2. Kim J, Cha MJ, Lee DH, Lee HS, Nam CM, Nam HS, Kim YD, Heo JH: The association between cerebral atherosclerosis and arterial stiffness in acute ischemic stroke. Atherosclerosis 2011, 219(2):887-891.
3. Villadoniga JI: A more accurate approach to molecular genetics analysis in vascular disease. Cardiovascular & Hematological Disorders Drug Targets 2008, 8(3):212-227.
4. Leon AS, Bronas UG: Dyslipidemia and Risk of Coronary Heart Disease: Role of Lifestyle Approaches for Its Management. American Journal of Lifestyle Medicine 2009, 3:257-273.
5. van Leuven SI, Franssen R, Kastelein JJ, Levi M, Stroes ES, Tak PP: Systemic inflammation as a risk factor for atherothrombosis. Rheumatology (Oxford, England) 2008, 47(1):3-7.
6. Fox CS, Cupples LA, Chazaro I, Polak JF, Wolf PA, D'Agostino RB, Ordovas JM, O'Donnell CJ: Genomewide linkage analysis for internal carotid artery intimal medial thickness: evidence for linkage to chromosome 12. American Journal of Human Genetics 2004, 74(2):253-261.
7. Ordovas JM: Genetic influences on blood lipids and cardiovascular disease risk: tools for primary prevention. The American Journal of Clinical Nutrition 2009, 89(5):1509s-1517s.
8. Davis BR, Arnett DK, Boerwinkle E, Ford CE, Leiendecker-Foster C, Miller MB, Black H, Eckfeldt JH: Antihypertensive therapy, the alpha-adducin polymorphism, and cardiovascular disease in high-risk hypertensive persons: the Genetics of Hypertension-Associated Treatment Study. The Pharmacogenomics Journal 2007, 7(2):112-122.
9. Crowther MA: Pathogenesis of atherosclerosis. Hematology / the Education Program of the American Society of Hematology American Society of Hematology Education Program 2005:436-441.
10. Schror K: Clinical pharmacology of the adenosine diphosphate (ADP) receptor antagonist, clopidogrel. Vascular Medicine (London, England) 1998, 3(3):247-251.
11. Yang Z, Ming XF: Recent advances in understanding endothelial dysfunction in atherosclerosis. Clinical Medicine & Research 2006, 4(1):53-65.
12. Napoli C, de Nigris F, Williams-Ignarro S, Pignalosa O, Sica V, Ignarro LJ: Nitric oxide and atherosclerosis: an update. Nitric Oxide : Biology and Chemistry / Official Journal of the Nitric Oxide Society 2006, 15(4):265-279.
13. Sitia S, Tomasoni L, Atzeni F, Ambrosio G, Cordiano C, Catapano A, Tramontana S, Perticone F, Naccarato P, Camici P, Picano E, Cortigiani L, Bevilacqua M, Milazzo L, Cusi D, Barlassina C, Sarzi-Puttini P, Turiel M: From endothelial dysfunction to atherosclerosis. Autoimmunity Reviews 2010, 9(12):830-834.
14. Deshmane SL, Kremlev S, Amini S, Sawaya BE: Monocyte chemoattractant protein-1 (MCP-1): an overview. Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research 2009, 29(6):313-326.
15. White FA, Sun J, Waters SM, Ma C, Ren D, Ripsch M, Steflik J, Cortright DN, Lamotte RH, Miller RJ: Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. Proc Natl Acad Sci U S A 2005, 102(39):14092-14097.
16. Khokha R, Murthy A, Weiss A: Metalloproteinases and their natural inhibitors in inflammation and immunity. Nature Reviews Immunology 2013, 13(9):649-665.
17. Monajemi H, Arkenbout EK, Pannekoek H: Gene expression in atherogenesis. Thromb Haemost 2001, 86(1):404-412.
18. Hellings WE, Moll FL, De Vries JP, Ackerstaff RG, Seldenrijk KA, Met R, Velema E, Derksen WJ, De Kleijn DP, Pasterkamp G: Atherosclerotic plaque composition and occurrence of restenosis after carotid endarterectomy. JAMA 2008, 299(5):547-554.
19. Korshunov VA, Schwartz SM, Berk BC: Vascular remodeling: hemodynamic and biochemical mechanisms underlying Glagov's phenomenon. Arteriosclerosis, Thrombosis, and Vascular Biology 2007, 27(8):1722-1728.
20. Di Tullio MR, Russo C, Jin Z, Sacco RL, Mohr JP, Homma S: Aortic arch plaques and risk of recurrent stroke and death. Circulation 2009, 119(17):2376-2382.
21. Getz GS, Reardon CA: Animal models of atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 2012, 32(5):1104-1115.
22. Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G, Nishigaki I: The vascular endothelium and human diseases. International Journal of Biological Sciences 2013, 9(10):1057-1069.
23. Al Mheid I, Quyyumi AA: Cell therapy in peripheral arterial disease. Angiology 2008, 59(6):705-716.
24. Ho KJ, Spite M, Owens CD, Lancero H, Kroemer AH, Pande R, Creager MA, Serhan CN, Conte MS: Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis. The American Journal of Pathology 2010, 177(4):2116-2123.
25. Daniel JM, Sedding DG: Circulating smooth muscle progenitor cells in arterial remodeling. Journal of Molecular and Cellular Cardiology 2011, 50(2):273-279.
26. Gonzalez-Navarro H, Abu Nabah YN, Vinue A, Andres-Manzano MJ, Collado M, Serrano M, Andres V: p19(ARF) deficiency reduces macrophage and vascular smooth muscle cell apoptosis and aggravates atherosclerosis. Journal of the American College of Cardiology 2010, 55(20):2258-2268.
27. Kockx MM, Knaapen MW: The role of apoptosis in vascular disease. The Journal of Pathology 2000, 190(3):267-280.
28. Clarke MC, Figg N, Maguire JJ, Davenport AP, Goddard M, Littlewood TD, Bennett MR: Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nature Medicine 2006, 12(9):1075-1080.
29. Tabas I: Pulling down the plug on atherosclerosis: finding the culprit in your heart. Nature Medicine 2011, 17(7):791-793.
30. Shi ZD, Tarbell JM: Fluid flow mechanotransduction in vascular smooth muscle cells and fibroblasts. Annals of Biomedical Engineering 2011, 39(6):1608-1619.
31. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC: Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999, 399(6736):597-601.
32. Navab M, Hough GP, Stevenson LW, Drinkwater DC, Laks H, Fogelman AM: Monocyte migration into the subendothelial space of a coculture of adult human aortic endothelial and smooth muscle cells. J Clin Invest 1988, 82(6):1853-1863.
33. Tang Y, Urs S, Boucher J, Bernaiche T, Venkatesh D, Spicer DB, Vary CP, Liaw L: Notch and transforming growth factor-beta (TGFbeta) signaling pathways cooperatively regulate vascular smooth muscle cell differentiation. J Biol Chem 2010, 285(23):17556-17563.
34. Beamish JA, He P, Kottke-Marchant K, Marchant RE: Molecular regulation of contractile smooth muscle cell phenotype: implications for vascular tissue engineering. Tissue Eng Part B Rev 2010, 16(5):467-491.
35. Yoshida Y, Sue W, Okano M, Oyama T, Yamane T, Mitsumata M: The effects of augmented hemodynamic forces on the progression and topography of atherosclerotic plaques. Ann N Y Acad Sci 1990, 598:256-273.
36. Stegemann JP, Dey NB, Lincoln TM, Nerem RM: Genetic modification of smooth muscle cells to control phenotype and function in vascular tissue engineering. Tissue Eng 2004, 10(1-2):189-199.
37. Acampora KB, Nagatomi J, Langan EM, 3rd, LaBerge M: Increased synthetic phenotype behavior of smooth muscle cells in response to in vitro balloon angioplasty injury model. Ann Vasc Surg 2010, 24(1):116-126.
38. Asada H, Paszkowiak J, Teso D, Alvi K, Thorisson A, Frattini JC, Kudo FA, Sumpio BE, Dardik A: Sustained orbital shear stress stimulates smooth muscle cell proliferation via the extracellular signal-regulated protein kinase 1/2 pathway. J Vasc Surg 2005, 42(4):772-780.
39. Sterpetti AV, Cucina A, D'Angelo LS, Cardillo B, Cavallaro A: Response of arterial smooth muscle cells to laminar flow. J Cardiovasc Surg (Torino) 1992, 33(5):619-624.
40. Kang H, Fan Y, Deng X: Vascular smooth muscle cell glycocalyx modulates shear-induced proliferation, migration, and NO production responses. Am J Physiol Heart Circ Physiol 2011, 300(1):H76-83.
41. Sterpetti AV, Cucina A, D'Angelo LS, Cardillo B, Cavallaro A: Shear stress modulates the proliferation rate, protein synthesis, and mitogenic activity of arterial smooth muscle cells. Surgery 1993, 113(6):691-699.
42. Ekstrand J, Razuvaev A, Folkersen L, Roy J, Hedin U: Tissue factor pathway inhibitor-2 is induced by fluid shear stress in vascular smooth muscle cells and affects cell proliferation and survival. J Vasc Surg 2010, 52(1):167-175.
43. Papadaki M, McIntire LV, Eskin SG: Effects of shear stress on the growth kinetics of human aortic smooth muscle cells in vitro. Biotechnol Bioeng 1996, 50(5):555-561.
44. Sterpetti AV, Cucina A, Santoro L, Cardillo B, Cavallaro A: Modulation of arterial smooth muscle cell growth by haemodynamic forces. Eur J Vasc Surg 1992, 6(1):16-20.
45. Sho M, Sho E, Singh TM, Komatsu M, Sugita A, Xu C, Nanjo H, Zarins CK, Masuda H: Subnormal shear stress-induced intimal thickening requires medial smooth muscle cell proliferation and migration. Exp Mol Pathol 2002, 72(2):150-160.
46. Palumbo R, Gaetano C, Antonini A, Pompilio G, Bracco E, Ronnstrand L, Heldin CH, Capogrossi MC: Different effects of high and low shear stress on platelet-derived growth factor isoform release by endothelial cells: consequences for smooth muscle cell migration. Arteriosclerosis, Thrombosis, and Vascular Biology 2002, 22(3):405-411.
47. Qi YX, Qu MJ, Long DK, Liu B, Yao QP, Chien S, Jiang ZL: Rho-GDP dissociation inhibitor alpha downregulated by low shear stress promotes vascular smooth muscle cell migration and apoptosis: a proteomic analysis. Cardiovascular Research 2008, 80(1):114-122.
48. Ueba H, Kawakami M, Yaginuma T: Shear stress as an inhibitor of vascular smooth muscle cell proliferation. Role of transforming growth factor-beta 1 and tissue-type plasminogen activator. Arteriosclerosis, Thrombosis, and Vascular Biology 1997, 17(8):1512-1516.
49. Goldman J, Zhong L, Liu SQ: Negative regulation of vascular smooth muscle cell migration by blood shear stress. Am J Physiol Heart Circ Physiol 2007, 292(2):H928-938.
50. Palumbo R, Gaetano C, Melillo G, Toschi E, Remuzzi A, Capogrossi MC: Shear stress downregulation of platelet-derived growth factor receptor-beta and matrix metalloprotease-2 is associated with inhibition of smooth muscle cell invasion and migration. Circulation 2000, 102(2):225-230.
51. Garanich JS, Pahakis M, Tarbell JM: Shear stress inhibits smooth muscle cell migration via nitric oxide-mediated downregulation of matrix metalloproteinase-2 activity. Am J Physiol Heart Circ Physiol 2005, 288(5):H2244-2252.
52. Fitzgerald TN, Shepherd BR, Asada H, Teso D, Muto A, Fancher T, Pimiento JM, Maloney SP, Dardik A: Laminar shear stress stimulates vascular smooth muscle cell apoptosis via the Akt pathway. J Cell Physiol 2008, 216(2):389-395.
53. Haga M, Yamashita A, Paszkowiak J, Sumpio BE, Dardik A: Oscillatory shear stress increases smooth muscle cell proliferation and Akt phosphorylation. J Vasc Surg 2003, 37(6):1277-1284.
54. Wagner CT, Durante W, Christodoulides N, Hellums JD, Schafer AI: Hemodynamic forces induce the expression of heme oxygenase in cultured vascular smooth muscle cells. J Clin Invest 1997, 100(3):589-596.
55. Sumi T, Yamashita A, Matsuda S, Goto S, Nishihira K, Furukoji E, Sugimura H, Kawahara H, Imamura T, Kitamura K, Tamura S, Asada Y: Disturbed blood flow induces erosive injury to smooth muscle cell-rich neointima and promotes thrombus formation in rabbit femoral arteries. J Thromb Haemost 2010, 8(6):1394-1402.
56. Meng H, Wang Z, Hoi Y, Gao L, Metaxa E, Swartz DD, Kolega J: Complex hemodynamics at the apex of an arterial bifurcation induces vascular remodeling resembling cerebral aneurysm initiation. Stroke 2007, 38(6):1924-1931.
57. Metaxa E, Meng H, Kaluvala SR, Szymanski MP, Paluch RA, Kolega J: Nitric oxide-dependent stimulation of endothelial cell proliferation by sustained high flow. Am J Physiol Heart Circ Physiol 2008, 295(2):H736-742.
58. Wang S, Tarbell JM: Effect of fluid flow on smooth muscle cells in a 3-dimensional collagen gel model. Arteriosclerosis, Thrombosis, and Vascular Biology 2000, 20(10):2220-2225.
59. Tada S, Tarbell JM: Interstitial flow through the internal elastic lamina affects shear stress on arterial smooth muscle cells. Am J Physiol Heart Circ Physiol 2000, 278(5):H1589-1597.
60. Tada S, Tarbell JM: Flow through internal elastic lamina affects shear stress on smooth muscle cells (3D simulations). Am J Physiol Heart Circ Physiol 2002, 282(2):H576-584.
61. Shi ZD, Abraham G, Tarbell JM: Shear stress modulation of smooth muscle cell marker genes in 2-D and 3-D depends on mechanotransduction by heparan sulfate proteoglycans and ERK1/2. PLoS One 2010, 5(8):e12196.
62. Liu Y, Chan-Park MB: A biomimetic hydrogel based on methacrylated dextran-graft-lysine and gelatin for 3D smooth muscle cell culture. Biomaterials 2010, 31(6):1158-1170.
63. Jin L, Hastings NE, Blackman BR, Somlyo AV: Mechanical properties of the extracellular matrix alter expression of smooth muscle protein LPP and its partner palladin; relationship to early atherosclerosis and vascular injury. J Muscle Res Cell Motil 2009, 30(1-2):41-55.
64. Pang Y, Wang X, Lee D, Greisler HP: Dynamic quantitative visualization of single cell alignment and migration and matrix remodeling in 3-D collagen hydrogels under mechanical force. Biomaterials 2011, 32(15):3776-3783.
65. Liu SQ, Tieche C, Tang D, Alkema P: Pattern formation of vascular smooth muscle cells subject to nonuniform fluid shear stress: role of PDGF-beta receptor and Src. Am J Physiol Heart Circ Physiol 2003, 285(3):H1081-1090.
66. Ng CP, Hinz B, Swartz MA: Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J Cell Sci 2005, 118(Pt 20):4731-4739.
67. Orlandi A, Francesconi A, Marcellini M, Ferlosio A, Spagnoli LG: Role of ageing and coronary atherosclerosis in the development of cardiac fibrosis in the rabbit. Cardiovascular Research 2004, 64(3):544-552.
68. Coen M, Gabbiani G, Bochaton-Piallat ML: Myofibroblast-mediated adventitial remodeling: an underestimated player in arterial pathology. Arteriosclerosis, Thrombosis, and Vascular Biology 2011, 31(11):2391-2396.
69. Shi ZD, Ji XY, Qazi H, Tarbell JM: Interstitial flow promotes vascular fibroblast, myofibroblast, and smooth muscle cell motility in 3-D collagen I via upregulation of MMP-1. Am J Physiol Heart Circ Physiol 2009, 297(4):H1225-1234.
70. Shi ZD, Wang H, Tarbell JM: Heparan sulfate proteoglycans mediate interstitial flow mechanotransduction regulating MMP-13 expression and cell motility via FAK-ERK in 3D collagen. PLoS One 2011, 6(1):e15956.
71. Tarbell JM, Shi ZD: Effect of the glycocalyx layer on transmission of interstitial flow shear stress to embedded cells. Biomech Model Mechanobiol 2013, 12(1):111-121.
72. Shi ZD, Ji XY, Berardi DE, Qazi H, Tarbell JM: Interstitial flow induces MMP-1 expression and vascular SMC migration in collagen I gels via an ERK1/2-dependent and c-Jun-mediated mechanism. Am J Physiol Heart Circ Physiol 2010, 298(1):H127-135.
73. Tsai MC, Chen L, Zhou J, Tang Z, Hsu TF, Wang Y, Shih YT, Peng HH, Wang N, Guan Y, Chien S, Chiu JJ: Shear stress induces synthetic-to-contractile phenotypic modulation in smooth muscle cells via peroxisome proliferator-activated receptor alpha/delta activations by prostacyclin released by sheared endothelial cells. Circ Res 2009, 105(5):471-480.
74. Hastings NE, Simmers MB, McDonald OG, Wamhoff BR, Blackman BR: Atherosclerosis-prone hemodynamics differentially regulates endothelial and smooth muscle cell phenotypes and promotes pro-inflammatory priming. Am J Physiol Cell Physiol 2007, 293(6):C1824-1833.
75. Qi YX, Jiang J, Jiang XH, Wang XD, Ji SY, Han Y, Long DK, Shen BR, Yan ZQ, Chien S, Jiang ZL: PDGF-BB and TGF-{beta}1 on cross-talk between endothelial and smooth muscle cells in vascular remodeling induced by low shear stress. Proc Natl Acad Sci U S A 2011, 108(5):1908-1913.
76. Wang HQ, Huang LX, Qu MJ, Yan ZQ, Liu B, Shen BR, Jiang ZL: Shear stress protects against endothelial regulation of vascular smooth muscle cell migration in a coculture system. Endothelium 2006, 13(3):171-180.
77. Hsieh HJ, Li NQ, Frangos JA: Shear stress increases endothelial platelet-derived growth factor mRNA levels. Am J Physiol 1991, 260(2 Pt 2):H642-646.
78. Thomas JA, Deaton RA, Hastings NE, Shang Y, Moehle CW, Eriksson U, Topouzis S, Wamhoff BR, Blackman BR, Owens GK: PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns. Am J Physiol Heart Circ Physiol 2009, 296(2):H442-452.
79. Lau HK: Cytotoxicity of nitric oxide donors in smooth muscle cells is dependent on phenotype, and mainly due to apoptosis. Atherosclerosis 2003, 166(2):223-232.
80. Hendrickson RJ, Cappadona C, Yankah EN, Sitzmann JV, Cahill PA, Redmond EM: Sustained pulsatile flow regulates endothelial nitric oxide synthase and cyclooxygenase expression in co-cultured vascular endothelial and smooth muscle cells. Journal of Molecular and Cellular Cardiology 1999, 31(3):619-629.
81. Dirksen MT, van der Wal AC, van den Berg FM, van der Loos CM, Becker AE: Distribution of inflammatory cells in atherosclerotic plaques relates to the direction of flow. Circulation 1998, 98(19):2000-2003.
82. Hsieh PC, Kenagy RD, Mulvihill ER, Jeanette JP, Wang X, Chang CM, Yao Z, Ruzzo WL, Justice S, Hudkins KL, Alpers CE, Berceli S, Clowes AW: Bone morphogenetic protein 4: potential regulator of shear stress-induced graft neointimal atrophy. J Vasc Surg 2006, 43(1):150-158.
83. Fan L, Karino T: Effect of a disturbed flow on proliferation of the cells of a hybrid vascular graft. Biorheology 2010, 47(1):31-38.
84. Chiu JJ, Chen LJ, Chang SF, Lee PL, Lee CI, Tsai MC, Lee DY, Hsieh HP, Usami S, Chien S: Shear stress inhibits smooth muscle cell-induced inflammatory gene expression in endothelial cells: role of NF-kappaB. Arteriosclerosis, Thrombosis, and Vascular Biology 2005, 25(5):963-969.
85. Ross R: Atherosclerosis--an inflammatory disease. The New England Journal of Medicine 1999, 340(2):115-126.
86. Ross R, Glomset J, Kariya B, Raines E: Role of platelet factors in the growth of cells in culture. National Cancer Institute Monograph 1978(48):103-108.
87. Heldin CH, Westermark B, Wasteson A: Platelet-derived growth factor. Isolation by a large-scale procedure and analysis of subunit composition. The Biochemical journal 1981, 193(3):907-913.
88. Antoniades HN: Human platelet-derived growth factor (PDGF): purification of PDGF-I and PDGF-II and separation of their reduced subunits. Proc Natl Acad Sci U S A 1981, 78(12):7314-7317.
89. Raines EW, Ross R: Platelet-derived growth factor. I. High yield purification and evidence for multiple forms. J Biol Chem 1982, 257(9):5154-5160.
90. Seifert RA, Hart CE, Phillips PE, Forstrom JW, Ross R, Murray MJ, Bowen-Pope DF: Two different subunits associate to create isoform-specific platelet-derived growth factor receptors. J Biol Chem 1989, 264(15):8771-8778.
91. Gilbertson DG, Duff ME, West JW, Kelly JD, Sheppard PO, Hofstrand PD, Gao Z, Shoemaker K, Bukowski TR, Moore M, Feldhaus AL, Humes JM, Palmer TE, Hart CE: Platelet-derived growth factor C (PDGF-C), a novel growth factor that binds to PDGF alpha and beta receptor. J Biol Chem 2001, 276(29):27406-27414.
92. LaRochelle WJ, Jeffers M, McDonald WF, Chillakuru RA, Giese NA, Lokker NA, Sullivan C, Boldog FL, Yang M, Vernet C, Burgess CE, Fernandes E, Deegler LL, Rittman B, Shimkets J, Shimkets RA, Rothberg JM, Lichenstein HS: PDGF-D, a new protease-activated growth factor. Nature Cell Biology 2001, 3(5):517-521.
93. Heldin CH, Westermark B: Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 1999, 79(4):1283-1316.
94. Uutela M, Lauren J, Bergsten E, Li X, Horelli-Kuitunen N, Eriksson U, Alitalo K: Chromosomal location, exon structure, and vascular expression patterns of the human PDGFC and PDGFD genes. Circulation 2001, 103(18):2242-2247.
95. Taneda S, Hudkins KL, Topouzis S, Gilbertson DG, Ophascharoensuk V, Truong L, Johnson RJ, Alpers CE: Obstructive uropathy in mice and humans: potential role for PDGF-D in the progression of tubulointerstitial injury. J Am Soc Nephrol 2003, 14(10):2544-2555.
96. Heldin CH, Eriksson U, Ostman A: New members of the platelet-derived growth factor family of mitogens. Arch Biochem Biophys 2002, 398(2):284-290.
97. Floege J, Hudkins KL, Davis CL, Schwartz SM, Alpers CE: Expression of PDGF alpha-receptor in renal arteriosclerosis and rejecting renal transplants. J Am Soc Nephrol 1998, 9(2):211-223.
98. Rubin K, Tingstrom A, Hansson GK, Larsson E, Ronnstrand L, Klareskog L, Claesson-Welsh L, Heldin CH, Fellstrom B, Terracio L: Induction of B-type receptors for platelet-derived growth factor in vascular inflammation: possible implications for development of vascular proliferative lesions. Lancet 1988, 1(8599):1353-1356.
99. Lindner V, Reidy MA: Platelet-derived growth factor ligand and receptor expression by large vessel endothelium in vivo. The American Journal of Pathology 1995, 146(6):1488-1497.
100. Boring L, Gosling J, Cleary M, Charo IF: Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998, 394(6696):894-897.
101. Gosling J, Slaymaker S, Gu L, Tseng S, Zlot CH, Young SG, Rollins BJ, Charo IF: MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest 1999, 103(6):773-778.
102. Ni W, Egashira K, Kitamoto S, Kataoka C, Koyanagi M, Inoue S, Imaizumi K, Akiyama C, Nishida KI, Takeshita A: New anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein E-knockout mice. Circulation 2001, 103(16):2096-2101.
103. Barrett TB, Benditt EP: sis (platelet-derived growth factor B chain) gene transcript levels are elevated in human atherosclerotic lesions compared to normal artery. Proc Natl Acad Sci U S A 1987, 84(4):1099-1103.
104. Ross R, Masuda J, Raines EW, Gown AM, Katsuda S, Sasahara M, Malden LT, Masuko H, Sato H: Localization of PDGF-B protein in macrophages in all phases of atherogenesis. Science 1990, 248(4958):1009-1012.
105. Evanko SP, Raines EW, Ross R, Gold LI, Wight TN: Proteoglycan distribution in lesions of atherosclerosis depends on lesion severity, structural characteristics, and the proximity of platelet-derived growth factor and transforming growth factor-beta. The American Journal of Pathology 1998, 152(2):533-546.
106. Wilcox JN, Smith KM, Williams LT, Schwartz SM, Gordon D: Platelet-derived growth factor mRNA detection in human atherosclerotic plaques by in situ hybridization. J Clin Invest 1988, 82(3):1134-1143.
107. Tanizawa S, Ueda M, van der Loos CM, van der Wal AC, Becker AE: Expression of platelet derived growth factor B chain and beta receptor in human coronary arteries after percutaneous transluminal coronary angioplasty: an immunohistochemical study. Heart 1996, 75(6):549-556.
108. Abe J, Deguchi J, Takuwa Y, Hara K, Ikari Y, Tamura T, Ohno M, Kurokawa K: Tyrosine phosphorylation of platelet derived growth factor beta receptors in coronary artery lesions: implications for vascular remodelling after directional coronary atherectomy and unstable angina pectoris. Heart 1998, 79(4):400-406.
109. Giese NA, Marijianowski MM, McCook O, Hancock A, Ramakrishnan V, Fretto LJ, Chen C, Kelly AB, Koziol JA, Wilcox JN, Hanson SR: The role of alpha and beta platelet-derived growth factor receptor in the vascular response to injury in nonhuman primates. Arteriosclerosis, Thrombosis, and Vascular Biology 1999, 19(4):900-909.
110. Ueda M, Becker AE, Kasayuki N, Kojima A, Morita Y, Tanaka S: In situ detection of platelet-derived growth factor-A and -B chain mRNA in human coronary arteries after percutaneous transluminal coronary angioplasty. The American Journal of Pathology 1996, 149(3):831-843.
111. Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI: The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci U S A 2000, 97(16):9052-9057.
112. Mondy JS, Lindner V, Miyashiro JK, Berk BC, Dean RH, Geary RL: Platelet-derived growth factor ligand and receptor expression in response to altered blood flow in vivo. Circ Res 1997, 81(3):320-327.
113. Zerwes HG, Risau W: Polarized secretion of a platelet-derived growth factor-like chemotactic factor by endothelial cells in vitro. The Journal of Cell Biology 1987, 105(5):2037-2041.
114. Clowes AW, Kirkman TR, Reidy MA: Mechanisms of arterial graft healing. Rapid transmural capillary ingrowth provides a source of intimal endothelium and smooth muscle in porous PTFE prostheses. The American Journal of Pathology 1986, 123(2):220-230.
115. Kraiss LW, Geary RL, Mattsson EJ, Vergel S, Au YP, Clowes AW: Acute reductions in blood flow and shear stress induce platelet-derived growth factor-A expression in baboon prosthetic grafts. Circ Res 1996, 79(1):45-53.
116. Clowes AW, Reidy MA, Clowes MM: Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. Lab Invest 1983, 49(3):327-333.
117. Fingerle J, Au YP, Clowes AW, Reidy MA: Intimal lesion formation in rat carotid arteries after endothelial denudation in absence of medial injury. Arteriosclerosis 1990, 10(6):1082-1087.
118. Han DK, Haudenschild CC, Hong MK, Tinkle BT, Leon MB, Liau G: Evidence for apoptosis in human atherogenesis and in a rat vascular injury model. The American Journal of Pathology 1995, 147(2):267-277.
119. Jackson CL, Raines EW, Ross R, Reidy MA: Role of endogenous platelet-derived growth factor in arterial smooth muscle cell migration after balloon catheter injury. Arterioscler Thromb 1993, 13(8):1218-1226.
120. Panek RL, Dahring TK, Olszewski BJ, Keiser JA: PDGF receptor protein tyrosine kinase expression in the balloon-injured rat carotid artery. Arteriosclerosis, Thrombosis, and Vascular Biology 1997, 17(7):1283-1288.
121. Lewis CD, Olson NE, Raines EW, Reidy MA, Jackson CL: Modulation of smooth muscle proliferation in rat carotid artery by platelet-derived mediators and fibroblast growth factor-2. Platelets 2001, 12(6):352-358.
122. Ferns GA, Raines EW, Sprugel KH, Motani AS, Reidy MA, Ross R: Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science 1991, 253(5024):1129-1132.
123. Hoch RV, Soriano P: Roles of PDGF in animal development. Development 2003,130(20):4769-4784.
124. Johnson DG, Walker CL: Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol 1999, 39:295-312.
125. Lundberg AS, Weinberg RA: Control of the cell cycle and apoptosis. Eur J Cancer 1999, 35(14):1886-1894.
126. Evans T, Rosenthal ET, Youngblom J, Distel D, Hunt T: Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 1983, 33(2):389-396.
127. Rosenthal ET, Hunt T, Ruderman JV: Selective translation of mRNA controls the pattern of protein synthesis during early development of the surf clam, Spisula solidissima. Cell 1980, 20(2):487-494.
128. Morgan DO: Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 1997, 13:261-291.
129. Draetta GF: Mammalian G1 cyclins. Curr Opin Cell Biol 1994, 6(6):842-846.
130. Hunter T, Pines J: Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell 1994, 79(4):573-582.
131. Pines J: Cyclins and their associated cyclin-dependent kinases in the human cell cycle. Biochem Soc Trans 1993, 21(4):921-925.
132. Pines J: Cyclins and cyclin-dependent kinases: take your partners. Trends Biochem Sci 1993, 18(6):195-197.
133. Shapiro GI, Harper JW: Anticancer drug targets: cell cycle and checkpoint control. J Clin Invest 1999, 104(12):1645-1653.
134. Pines J: Four-dimensional control of the cell cycle. Nature cell biology 1999, 1(3):E73-79.
135. Pines J: Cell cycle. Checkpoint on the nuclear frontier. Nature 1999, 397(6715):104-105.
136. Pietenpol JA, Stewart ZA: Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis. Toxicology 2002, 181-182:475-481.
137. Spirin KS, Simpson JF, Takeuchi S, Kawamata N, Miller CW, Koeffler HP: p27/Kip1 mutation found in breast cancer. Cancer Res 1996, 56(10):2400-2404.
138. Hartwell LH, Weinert TA: Checkpoints: controls that ensure the order of cell cycle events. Science 1989, 246(4930):629-634.
139. Iliakis G, Wang Y, Guan J, Wang H: DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene 2003, 22(37):5834-5847.
140. Sherr CJ, Roberts JM: Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 1995, 9(10):1149-1163.
141. Burke DJ: Complexity in the spindle checkpoint. Curr Opin Genet Dev 2000, 10(1):26-31.
142. Sorger PK, Dobles M, Tournebize R, Hyman AA: Coupling cell division and cell death to microtubule dynamics. Curr Opin Cell Biol 1997, 9(6):807-814.
143. Andrés V: Control of vascular cell proliferation and migration by cyclin-dependent kinase signalling: new perspectives and therapeutic potential. Cardiovasc Res 2004,63(1):11-21.
144. Sherr CJ, Roberts JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999, 13(12):1501-1512.
145. Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW: Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 1998, 12(19):3008-3019.
146. Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M: Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol 1997, 17(9):5598-5611.
147. Kouzarides T: Histone acetylases and deacetylases in cell proliferation. Curr Opin Genet Dev 1999, 9(1):40-48.
148. Lavoie JN, L'Allemain G, Brunet A, Muller R, Pouyssegur J: Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem 1996, 271(34):20608-20616.
149. Peeper DS, Upton TM, Ladha MH, Neuman E, Zalvide J, Bernards R, DeCaprio JA, Ewen ME: Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein. Nature 1997, 386(6621):177-181.
150. Serrano M, Gomez-Lahoz E, DePinho RA, Beach D, Bar-Sagi D: Inhibition of ras-induced proliferation and cellular transformation by p16INK4. Science 1995, 267(5195):249-252.
151. Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ: The p21(Cip1) and p27(Kip1) CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J 1999, 18(6):1571-1583.
152. Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE: Cyclin E-CDK2 is a regulator of p27Kip1. Genes Dev 1997, 11(11):1464-1478.
153. Takuwa N, Takuwa Y: Ras activity late in G1 phase required for p27kip1 downregulation, passage through the restriction point, and entry into S phase in growth factor-stimulated NIH 3T3 fibroblasts. Mol Cell Biol 1997, 17(9):5348-5358.
154. Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M: Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 1995, 269(5224):682-685.
155. Zhu X, Assoian RK: Integrin-dependent activation of MAP kinase: a link to shape-dependent cell proliferation. Mol Biol Cell 1995, 6(3):273-282.
156. Renshaw MW, Ren XD, Schwartz MA: Growth factor activation of MAP kinase requires cell adhesion. EMBO J 1997, 16(18):5592-5599.
157. Schulze A, Zerfass K, Spitkovsky D, Middendorp S, Berges J, Helin K, Jansen-Durr P, Henglein B: Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. Proc Natl Acad Sci U S A 1995, 92(24):11264-11268.
158. Roovers K, Davey G, Zhu X, Bottazzi ME, Assoian RK: Alpha5beta1 integrin controls cyclin D1 expression by sustaining mitogen-activated protein kinase activity in growth factor-treated cells. Mol Biol Cell 1999, 10(10):3197-3204.
159. Igishi T, Fukuhara S, Patel V, Katz BZ, Yamada KM, Gutkind JS: Divergent signaling pathways link focal adhesion kinase to mitogen-activated protein kinase cascades. Evidence for a role of paxillin in c-Jun NH(2)-terminal kinase activation. J Biol Chem 1999, 274(43):30738-30746.
160. Schlaepfer DD, Hunter T: Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation of c-Src. J Biol Chem 1997, 272(20):13189-13195.
161. Wary KK, Mainiero F, Isakoff SJ, Marcantonio EE, Giancotti FG: The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell 1996, 87(4):733-743.
162. Fang F, Orend G, Watanabe N, Hunter T, Ruoslahti E: Dependence of cyclin E-CDK2 kinase activity on cell anchorage. Science 1996, 271(5248):499-502.
163. Kasid U, Suy S, Dent P, Ray S, Whiteside TL, Sturgill TW: Activation of Raf by ionizing radiation. Nature 1996, 382(6594):813-816.
164. Abbott DW, Holt JT: Mitogen-activated protein kinase kinase 2 activation is essential for progression through the G2/M checkpoint arrest in cells exposed to ionizing radiation. J Biol Chem 1999, 274(5):2732-2742.
165. Wright JH, Munar E, Jameson DR, Andreassen PR, Margolis RL, Seger R, Krebs EG: Mitogen-activated protein kinase kinase activity is required for the G(2)/M transition of the cell cycle in mammalian fibroblasts. Proc Natl Acad Sci U S A 1999, 96(20):11335-11340.
166. Kato Y, Kravchenko VV, Tapping RI, Han J, Ulevitch RJ, Lee JD: BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J 1997, 16(23):7054-7066.
167. English JM, Pearson G, Hockenberry T, Shivakumar L, White MA, Cobb MH: Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control. J Biol Chem 1999, 274(44):31588-31592.
168. Kamakura S, Moriguchi T, Nishida E: Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. J Biol Chem 1999, 274(37):26563-26571.
169. Kato Y, Tapping RI, Huang S, Watson MH, Ulevitch RJ, Lee JD: Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature 1998, 395(6703):713-716.
170. Wang S, Nath N, Minden A, Chellappan S: Regulation of Rb and E2F by signal transduction cascades: divergent effects of JNK1 and p38 kinases. EMBO J 1999, 18(6):1559-1570.
171. Schreiber M, Kolbus A, Piu F, Szabowski A, Mohle-Steinlein U, Tian J, Karin M, Angel P, Wagner EF: Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev 1999, 13(5):607-619.
172. Ellinger-Ziegelbauer H, Kelly K, Siebenlist U: Cell cycle arrest and reversion of Ras-induced transformation by a conditionally activated form of mitogen-activated protein kinase kinase kinase 3. Mol Cell Biol 1999, 19(5):3857-3868.
173. Takenaka K, Moriguchi T, Nishida E: Activation of the protein kinase p38 in the spindle assembly checkpoint and mitotic arrest. Science 1998, 280(5363):599-602.
174. McCubrey JA, Blalock WL, Saleh O, Pearce M, Burrows C, Steelman LS, Lee JT, Franklin RA, Oberhaus SM, Moye PW, Doshi PD, McKearn JP: Enhanced ability of daniplestim and myelopoietin-1 to suppress apoptosis in human hematopoietic cells. Leukemia 2001, 15(8):1203-1216.
175. Srinivasa SP, Doshi PD: Extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways cooperate in mediating cytokine-induced proliferation of a leukemic cell line. Leukemia 2002, 16(2):244-253.
176. Blalock WL, Weinstein-Oppenheimer C, Chang F, Hoyle PE, Wang XY, Algate PA, Franklin RA, Oberhaus SM, Steelman LS, McCubrey JA: Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs. Leukemia 1999, 13(8):1109-1166.
177. Lee JT, Jr., McCubrey JA: Targeting the Raf kinase cascade in cancer therapy--novel molecular targets and therapeutic strategies. Expert Opin Ther Targets 2002, 6(6):659-678.
178. Scheid MP, Woodgett JR: PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2001, 2(10):760-768.
179. Duronio V, Scheid MP, Ettinger S: Downstream signalling events regulated by phosphatidylinositol 3-kinase activity. Cell Signal 1998, 10(4):233-239.
180. Pacold ME, Suire S, Perisic O, Lara-Gonzalez S, Davis CT, Walker EH, Hawkins PT, Stephens L, Eccleston JF, Williams RL: Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell 2000, 103(6):931-943.
181. Djordjevic S, Driscoll PC: Structural insight into substrate specificity and regulatory mechanisms of phosphoinositide 3-kinases. Trends Biochem Sci 2002, 27(8):426-432.
182. Chan TO, Rodeck U, Chan AM, Kimmelman AC, Rittenhouse SE, Panayotou G, Tsichlis PN: Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit. Cancer Cell 2002, 1(2):181-191.
183. Yan J, Roy S, Apolloni A, Lane A, Hancock JF: Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J Biol Chem 1998, 273(37):24052-24056.
184. Vazquez F, Sellers WR: The PTEN tumor suppressor protein: an antagonist of phosphoinositide 3-kinase signaling. Biochimica et Biophysica Acta 2000, 1470(1):M21-35.
185. Taylor V, Wong M, Brandts C, Reilly L, Dean NM, Cowsert LM, Moodie S, Stokoe D: 5' phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells. Mol Cell Biol 2000, 20(18):6860-6871.
186. Carnero A, Hannon GJ: The INK4 family of CDK inhibitors. Curr Top Microbiol Immunol 1998, 227:43-55.
187. Nakano N, Urasawa K, Takagi Y, Saito T, Kaneta S, Ishikawa S, Higashi H, Tsutsui H, Hatakeyama M, Kitabatake A: Downregulation of cyclin-dependent kinase inhibitor; p57(kip2), is involved in the cell cycle progression of vascular smooth muscle cells. Biochem Biophys Res Commun 2005, 338(3):1661-1667.
188. Hu Q, Klippel A, Muslin AJ, Fantl WJ, Williams LT: Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase. Science 1995, 268(5207):100-102.
189. Kaestner KH, Knochel W, Martinez DE: Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev 2000, 14(2):142-146.
190. Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL: PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nature Medicine 2002, 8(10):1145-1152.
191. Muraille E, Pesesse X, Kuntz C, Erneux C: Distribution of the src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells. The Biochemical Journal 1999, 342 Pt 3:697-705.
192. Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M: Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nature Medicine 2002, 8(10):1136-1144.
193. Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R, Franssen E, Slingerland JM: PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nature Medicine 2002, 8(10):1153-1160.
194. Diehl JA, Cheng M, Roussel MF, Sherr CJ: Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998, 12(22):3499-3511.
195. Chang F, Steelman LS, McCubrey JA: Raf-induced cell cycle progression in human TF-1 hematopoietic cells. Cell Cycle 2002, 1(3):220-226.
196. Lloyd AC, Obermuller F, Staddon S, Barth CF, McMahon M, Land H: Cooperating oncogenes converge to regulate cyclin/cdk complexes. Genes Dev 1997, 11(5):663-677.
197. Blalock WL, Pearce M, Steelman LS, Franklin RA, McCarthy SA, Cherwinski H, McMahon M, McCubrey JA: A conditionally-active form of MEK1 results in autocrine tranformation of human and mouse hematopoietic cells. Oncogene 2000, 19(4):526-536.
198. Blalock WL, Pearce M, Chang F, Lee JT, Pohnert SC, Burrows C, Steelman LS, Franklin RA, McMahon M, McCubrey JA: Effects of inducible MEK1 activation on the cytokine dependency of lymphoid cells. Leukemia 2001, 15(5):794-807.
199. Reusch HP, Zimmermann S, Schaefer M, Paul M, Moelling K: Regulation of Raf by Akt controls growth and differentiation in vascular smooth muscle cells. J Biol Chem 2001, 276(36):33630-33637.
200. Moelling K, Schad K, Bosse M, Zimmermann S, Schweneker M: Regulation of Raf-Akt Cross-talk. J Biol Chem 2002, 277(34):31099-31106.
201. Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA: Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J 1999, 18(11):3024-3033.
202. Gonzalez-Robayna IJ, Falender AE, Ochsner S, Firestone GL, Richards JS: Follicle-Stimulating hormone (FSH) stimulates phosphorylation and activation of protein kinase B (PKB/Akt) and serum and glucocorticoid-lnduced kinase (Sgk): evidence for A kinase-independent signaling by FSH in granulosa cells. Mol Endocrinol 2000, 14(8):1283-1300.
203. Kobayashi T, Deak M, Morrice N, Cohen P: Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase. The Biochemical Journal 1999, 344 Pt 1:189-197.
204. Chang F, McCubrey JA: P21(Cip1) induced by Raf is associated with increased Cdk4 activity in hematopoietic cells. Oncogene 2001, 20(32):4354-4364.
205. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997, 275(5308):1943-1947.
206. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK: The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A 1998, 95(23):13513-13518.
207. Suzuki J, Kaziro Y, Koide H: An activated mutant of R-Ras inhibits cell death caused by cytokine deprivation in BaF3 cells in the presence of IGF-I. Oncogene 1997, 15(14):1689-1697.
208. Rodriguez-Viciana P, Marte BM, Warne PH, Downward J: Phosphatidylinositol 3' kinase: one of the effectors of Ras. Philos Trans R Soc Lond B Biol Sci 1996, 351(1336):225-231; discussion 231-222.
209. Graff JR, Konicek BW, McNulty AM, Wang Z, Houck K, Allen S, Paul JD, Hbaiu A, Goode RG, Sandusky GE, Vessella RL, Neubauer BL: Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem 2000, 275(32):24500-24505.
210. Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR: Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A 1996, 93(8):3636-3641.
211. Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, Tsichlis PN, Testa JR: AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci U S A 1992, 89(19):9267-9271.
212. Scheid MP, Huber M, Damen JE, Hughes M, Kang V, Neilsen P, Prestwich GD, Krystal G, Duronio V: Phosphatidylinositol (3,4,5)P3 is essential but not sufficient for protein kinase B (PKB) activation; phosphatidylinositol (3,4)P2 is required for PKB phosphorylation at Ser-473: studies using cells from SH2-containing inositol-5-phosphatase knockout mice. J Biol Chem 2002, 277(11):9027-9035.
213. Jimeno J, Faircloth G, Sousa-Faro JF, Scheuer P, Rinehart K: New Marine Derived Anticancer Therapeutics ─ A Journey from the Sea to Clinical Trials. Marine Drugs 2004, 2:12-29.
214. Pomponi SA: The bioprocess-technological potential of the sea. J Biotechnol 1999, 70:5-13.
215. Kijjoa A, Swangwong P: Drugs and cosmetics from the sea. Marine Drugs 2004, 2:73-82.
216. Ruggieri GD: Drugs from the sea. Science 1976, 194(4264):491-497.
217. Colwell RR: Fulfilling the promise of biotechnology. Biotechnol Adv 2002, 20(3-4):215-228.
218. Nigrelli RF, Stempien MF, Jr., Ruggieri GD, Liguori VR, Cecil JT: Substances of potential biomedical importance from marine organisms. Fed Proc 1967, 26(4):1197-1205.
219. Faulkner DJ: Marine natural products. Nat Prod Rep 2002, 19(1):1-48.
220. Bringmann G, Lang G, Muhlbacher J, Schaumann K, Steffens S, Rytik PG, Hentschel U, Morschhauser J, Muller WE: Sorbicillactone A: a structurally unprecedented bioactive novel-type alkaloid from a sponge-derived fungus. Prog Mol Subcell Biol 2003, 37:231-253.
221. Burres NS, Barber DA, Gunasekera SP, Shen LL, Clement JJ: Antitumor activity and biochemical effects of topsentin. Biochemical Pharmacology 1991, 42(4):745-751.
222. Cho J, Kim Y: Sharks: a potential source of antiangiogenic factors and tumor treatments. Mar Biotechnol (NY) 2002, 4(6):521-525.
223. Clamp A, Jayson GC: The clinical development of the bryostatins. Anticancer Drugs 2002, 13(7):673-683.
224. Haefner B: Drugs from the deep: marine natural products as drug candidates. Drug Discov Today 2003, 8(12):536-544.
225. Hentschel U, Fieseler L, Wehrl M, Gernert C, Steinert M, Hacker J, Horn M: Microbial diversity of marine sponges. Prog Mol Subcell Biol 2003, 37:59-88.
226. Imada C: Enzyme inhibitors of marine microbial origin with pharmaceutical importance. Mar Biotechnol (NY) 2004, 6(3):193-198.
227. Isbrucker RA, Cummins J, Pomponi SA, Longley RE, Wright AE: Tubulin polymerizing activity of dictyostatin-1, a polyketide of marine sponge origin. Biochemical Pharmacology 2003, 66(1):75-82.
228. Jha RK, Zirong X: Biomedical compounds from marine organisms. Marine Drugs 2004, 2:123-146.
229. Thakur NL: Studies on some bioactivity aspects of selected marine organisms: Goa University (India) 2001.
230. Wen ZH, Chao CH, Wu MH, Sheu JH: A neuroprotective sulfone of marine origin and the in vivo anti-inflammatory activity of an analogue. European Journal of Medicinal Chemistry 2010, 45(12):5998-6004.
231. Jean YH, Chen WF, Duh CY, Huang SY, Hsu CH, Lin CS, Sung CS, Chen IM, Wen ZH: Inducible nitric oxide synthase and cyclooxygenase-2 participate in anti-inflammatory and analgesic effects of the natural marine compound lemnalol from Formosan soft coral Lemnalia cervicorni. European Journal of Pharmacology 2008, 578(2-3):323-331.
232. Jean YH, Chen WF, Sung CS, Duh CY, Huang SY, Lin CS, Tai MH, Tzeng SF, Wen ZH: Capnellene, a natural marine compound derived from soft coral, attenuates chronic constriction injury-induced neuropathic pain in rats. British Journal of Pharmacology 2009, 158(3):713-725.
233. Chen SC, Chien YC, Pan CH, Sheu JH, Chen CY, Wu CH: Inhibitory effect of dihydroaustrasulfone alcohol on the migration of human non-small cell lung carcinoma A549 cells and the antitumor effect on a Lewis lung carcinoma-bearing tumor model in C57BL/6J mice. Marine Drugs 2014, 12(1):196-213.
234. Chen WL, Qian Y, Meng WF, Pang JY, Lin YC, Guan YY, Chen SP, Liu J, Pei Z, Wang GL: A novel marine compound xyloketal B protects against oxidized LDL-induced cell injury in vitro. Biochemical Pharmacology 2009, 78(8):941-950.
235. Redmond EM, Cahill PA, Hirsch M, Wang YN, Sitzmann JV, Okada SS: Effect of pulse pressure on vascular smooth muscle cell migration: the role of urokinase and matrix metalloproteinase. Thromb Haemost 1999, 81(2):293-300.
236. Berger M, Rubinraut E, Barshack I, Roth A, Keren G, George J: Zinc reduces intimal hyperplasia in the rat carotid injury model. Atherosclerosis 2004, 175(2):229-234.
237. Li S, Tanaka H, Wang HH, Yoshiyama S, Kumagai H, Nakamura A, Brown DL, Thatcher SE, Wright GL, Kohama K: Intracellular signal transduction for migration and actin remodeling in vascular smooth muscle cells after sphingosylphosphorylcholine stimulation. Am J Physiol Heart Circ Physiol 2006, 291(3):H1262-1272.
238. Muslin AJ: MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. Clin Sci (Lond) 2008, 115(7):203-218.
239. Zhan Y, Kim S, Izumi Y, Izumiya Y, Nakao T, Miyazaki H, Iwao H: Role of JNK, p38, and ERK in platelet-derived growth factor-induced vascular proliferation, migration, and gene expression. Arteriosclerosis, Thrombosis, and Vascular biology 2003, 23(5):795-801.
240. Johnson GL, Lapadat R: Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002, 298(5600):1911-1912.
241. Cantley LC: The phosphoinositide 3-kinase pathway. Science 2002, 296(5573):1655-1657.
242. Force T, Bonventre JV: Growth factors and mitogen-activated protein kinases. Hypertension 1998, 31(1 Pt 2):152-161.
243. Davis NE: Atherosclerosis--an inflammatory process. Journal of Insurance Medicine (New York, NY) 2005, 37(1):72-75.
244. Andres V: Control of vascular cell proliferation and migration by cyclin-dependent kinase signalling: new perspectives and therapeutic potential. Cardiovascular Research 2004, 63(1):11-21.
245. Marx SO, Jayaraman T, Go LO, Marks AR: Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res 1995, 76(3):412-417.
246. Schwartz SM, deBlois D, O'Brien ER: The intima. Soil for atherosclerosis and restenosis. Circ Res 1995, 77(3):445-465.
247. Ross R: Mechanisms of atherosclerosis--a review. Advances in Nephrology from the Necker Hospital 1990, 19:79-86.
248. Weintraub WS: The pathophysiology and burden of restenosis. Am J Cardiol 2007, 100(5a):3k-9k.
249. Owens GK, Kumar MS, Wamhoff BR: Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 2004, 84(3):767-801.
250. Braun-Dullaeus RC, Mann MJ, Sedding DG, Sherwood SW, von der Leyen HE, Dzau VJ: Cell cycle-dependent regulation of smooth muscle cell activation. Arteriosclerosis, Thrombosis, and Vascular Biology 2004, 24(5):845-850.
251. Braun-Dullaeus RC, Mann MJ, Dzau VJ: Cell cycle progression: new therapeutic target for vascular proliferative disease. Circulation 1998, 98(1):82-89.
252. Wei GL, Krasinski K, Kearney M, Isner JM, Walsh K, Andres V: Temporally and spatially coordinated expression of cell cycle regulatory factors after angioplasty. Circ Res 1997, 80(3):418-426.
253. Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ, Kato JY: D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol 1994, 14(3):2066-2076.
254. Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M: Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol 1995, 15(5):2612-2624.
255. Cobb MH, Boulton TG, Robbins DJ: Extracellular signal-regulated kinases: ERKs in progress. Cell Regulation 1991, 2(12):965-978.
256. Nagata N, Niwa Y, Nakaya Y: A novel 31-amino-acid-length endothelin, ET-1(1-31), can act as a biologically active peptide for vascular smooth muscle cells. Biochem Biophys Res Commun 2000, 275(2):595-600.
257. Kondo T, Konishi F, Inui H, Inagami T: Differing signal transductions elicited by three isoforms of platelet-derived growth factor in vascular smooth muscle cells. J Biol Chem 1993, 268(6):4458-4464.
258. Jiang B, Yamamura S, Nelson PR, Mureebe L, Kent KC: Differential effects of platelet-derived growth factor isotypes on human smooth muscle cell proliferation and migration are mediated by distinct signaling pathways. Surgery 1996, 120(2):427-431.
259. Kakishita H, Hattori Y: Vascular smooth muscle cell activation and growth by 4-hydroxynonenal. Life Sci 2001, 69(6):689-697.
260. Shan R, Price JO, Gaarde WA, Monia BP, Krantz SB, Zhao ZJ: Distinct roles of JNKs/p38 MAP kinase and ERKs in apoptosis and survival of HCD-57 cells induced by withdrawal or addition of erythropoietin. Blood 1999, 94(12):4067-4076.
261. Berra E, Diaz-Meco MT, Moscat J: The activation of p38 and apoptosis by the inhibition of Erk is antagonized by the phosphoinositide 3-kinase/Akt pathway. J Biol Chem 1998, 273(17):10792-10797.
262. Welham MJ, Duronio V, Sanghera JS, Pelech SL, Schrader JW: Multiple hemopoietic growth factors stimulate activation of mitogen-activated protein kinase family members. J Immunol 1992, 149(5):1683-1693.
263. Virdee K, Tolkovsky AM: Inhibition of p42 and p44 mitogen-activated protein kinase activity by PD98059 does not suppress nerve growth factor-induced survival of sympathetic neurones. Journal of Neurochemistry 1996, 67(5):1801-1805.
264. Toker A, Cantley LC: Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 1997, 387(6634):673-676.
265. Muto A, Fitzgerald TN, Pimiento JM, Maloney SP, Teso D, Paszkowiak JJ, Westvik TS, Kudo FA, Nishibe T, Dardik A: Smooth muscle cell signal transduction: implications of vascular biology for vascular surgeons. J Vasc Surg 2007, 45 Suppl A:A15-24.
266. Sachinidis A, Locher R, Vetter W, Tatje D, Hoppe J: Different effects of platelet-derived growth factor isoforms on rat vascular smooth muscle cells. J Biol Chem 1990, 265(18):10238-10243.
267. Heldin CH, Ostman A, Ronnstrand L: Signal transduction via platelet-derived growth factor receptors. Biochimica et Biophysica Acta 1998, 1378(1):F79-113.
268. Gharibi B, Ghuman MS, Hughes FJ: Akt- and Erk-mediated regulation of proliferation and differentiation during PDGFRbeta-induced MSC self-renewal. Journal of Cellular and Molecular Medicine 2012, 16(11):2789-2801.
269. Jung F, Haendeler J, Goebel C, Zeiher AM, Dimmeler S: Growth factor-induced phosphoinositide 3-OH kinase/Akt phosphorylation in smooth muscle cells: induction of cell proliferation and inhibition of cell death. Cardiovascular Research 2000, 48(1):148-157.
270. Crews CM, Alessandrini A, Erikson RL: The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science 1992, 258(5081):478-480.
271. Hemmings BA: Akt signaling: linking membrane events to life and death decisions. Science 1997, 275(5300):628-630.
272. Franke TF, Kaplan DR, Cantley LC: PI3K: downstream AKTion blocks apoptosis. Cell 1997, 88(4):435-437.
273. Kulik G, Klippel A, Weber MJ: Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol Cell Biol 1997, 17(3):1595-1606.
274. Lim HJ, Lee S, Park JH, Lee KS, Choi HE, Chung KS, Lee HH, Park HY: PPAR delta agonist L-165041 inhibits rat vascular smooth muscle cell proliferation and migration via inhibition of cell cycle. Atherosclerosis 2009, 202(2):446-454.
275. Dzau VJ, Braun-Dullaeus RC, Sedding DG: Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nature Medicine 2002, 8(11):1249-1256.
276. Ross R: Cell biology of atherosclerosis. Annu Rev Physiol 1995, 57:791-804.
277. Gorski DH, Walsh K: Mitogen-responsive nuclear factors that mediate growth control signals in vascular myocytes. Cardiovascular Research 1995, 30(4):585-592.
278. Wang JM, Sica A, Peri G, Walter S, Padura IM, Libby P, Ceska M, Lindley I, Colotta F, Mantovani A: Expression of monocyte chemotactic protein and interleukin-8 by cytokine-activated human vascular smooth muscle cells. Arterioscler Thromb 1991, 11(5):1166-1174.
279. Tsouknos A, Nash GB, Rainger GE: Monocytes initiate a cycle of leukocyte recruitment when cocultured with endothelial cells. Atherosclerosis 2003, 170(1):49-58.
280. Rainger GE, Nash GB: Cellular pathology of atherosclerosis: smooth muscle cells prime cocultured endothelial cells for enhanced leukocyte adhesion. Circ Res 2001, 88(6):615-622.
281. Landry DB, Couper LL, Bryant SR, Lindner V: Activation of the NF-kappa B and I kappa B system in smooth muscle cells after rat arterial injury. Induction of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. The American Journal of Pathology 1997, 151(4):1085-1095.
282. Porreca E, Di Febbo C, Reale M, Castellani ML, Baccante G, Barbacane R, Conti P, Cuccurullo F, Poggi A: Monocyte chemotactic protein 1 (MCP-1) is a mitogen for cultured rat vascular smooth muscle cells. J Vasc Res 1997, 34(1):58-65.
283. Yue TL, Wang X, Sung CP, Olson B, McKenna PJ, Gu JL, Feuerstein GZ: Interleukin-8. A mitogen and chemoattractant for vascular smooth muscle cells. Circ Res 1994, 75(1):1-7.
284. Russo G, Leopold JA, Loscalzo J: Vasoactive substances: nitric oxide and endothelial dysfunction in atherosclerosis. Vascul Pharmacol 2002, 38(5):259-269.
285. Zimmerman MA, Selzman CH, Reznikov LL, Miller SA, Raeburn CD, Emmick J, Meng X, Harken AH: Lack of TNF-alpha attenuates intimal hyperplasia after mouse carotid artery injury. Am J Physiol Regul Integr Comp Physiol 2002, 283(2):R505-512.
286. Fujita M, Shannon JM, Irvin CG, Fagan KA, Cool C, Augustin A, Mason RJ: Overexpression of tumor necrosis factor-alpha produces an increase in lung volumes and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2001, 280(1):L39-49.
287. Lambert CM, Roy M, Meloche J, Robitaille GA, Agharazii M, Richard DE, Bonnet S: Tumor necrosis factor inhibitors as novel therapeutic tools for vascular remodeling diseases. Am J Physiol Heart Circ Physiol 2010, 299(4):H995-1001.
288. Han Y, Runge MS, Brasier AR: Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors. Circ Res 1999, 84(6):695-703.
289. von Kanel R, Mills PJ, Mausbach BT, Dimsdale JE, Patterson TL, Ziegler MG, Ancoli-Israel S, Allison M, Chattillion EA, Grant I: Effect of Alzheimer caregiving on circulating levels of C-reactive protein and other biomarkers relevant to cardiovascular disease risk: a longitudinal study. Gerontology 2012, 58(4):354-365.
290. Calabro P, Willerson JT, Yeh ET: Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells. Circulation 2003, 108(16):1930-1932.
291. Verma S, Kuliszewski MA, Li SH, Szmitko PE, Zucco L, Wang CH, Badiwala MV, Mickle DA, Weisel RD, Fedak PW, Stewart DJ, Kutryk MJ: C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Circulation 2004, 109(17):2058-2067.
292. Wang CH, Li SH, Weisel RD, Fedak PW, Dumont AS, Szmitko P, Li RK, Mickle DA, Verma S: C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation 2003, 107(13):1783-1790.
293. Hage FG, Oparil S, Xing D, Chen YF, McCrory MA, Szalai AJ: C-reactive protein-mediated vascular injury requires complement. Arteriosclerosis, Thrombosis, and Vascular Biology 2010, 30(6):1189-1195.
294. Danesh J, Muir J, Wong YK, Ward M, Gallimore JR, Pepys MB: Risk factors for coronary heart disease and acute-phase proteins. A population-based study. Eur Heart J 1999, 20(13):954-959.
295. Intengan HD, Schiffrin EL: Structure and mechanical properties of resistance arteries in hypertension: role of adhesion molecules and extracellular matrix determinants. Hypertension 2000, 36(3):312-318.
296. Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty AM, Korsgaard N, Schiffrin EL, Heistad DD: Vascular remodeling. Hypertension 1996, 28(3):505-506.
297. Rensen SS, Doevendans PA, van Eys GJ: Regulation and characteristics of vascular smooth muscle cell phenotypic diversity. Neth Heart J 2007, 15(3):100-108.
298. Sinha S, Hoofnagle MH, Kingston PA, McCanna ME, Owens GK: Transforming growth factor-beta1 signaling contributes to development of smooth muscle cells from embryonic stem cells. Am J Physiol Cell Physiol 2004, 287(6):C1560-1568.
299. Shah NM, Groves AK, Anderson DJ: Alternative neural crest cell fates are instructively promoted by TGFbeta superfamily members. Cell 1996, 85(3):331-343.
300. Hirschi KK, Rohovsky SA, D'Amore PA: PDGF, TGF-beta, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. The Journal of Cell Biology 1998, 141(3):805-814.
301. Lindner V, Reidy MA: Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor. Proc Natl Acad Sci U S A 1991, 88(9):3739-3743.
302. Nugent MA, Karnovsky MJ, Edelman ER: Vascular cell-derived heparan sulfate shows coupled inhibition of basic fibroblast growth factor binding and mitogenesis in vascular smooth muscle cells. Circ Res 1993, 73(6):1051-1060.
303. Kawai-Kowase K, Sato H, Oyama Y, Kanai H, Sato M, Doi H, Kurabayashi M: Basic fibroblast growth factor antagonizes transforming growth factor-beta1-induced smooth muscle gene expression through extracellular signal-regulated kinase 1/2 signaling pathway activation. Arteriosclerosis, thrombosis, and vascular biology 2004, 24(8):1384-1390.
304. Tang Y, Yang X, Friesel RE, Vary CP, Liaw L: Mechanisms of TGF-beta-induced differentiation in human vascular smooth muscle cells. J Vasc Res 2011, 48(6):485-494.
305. Wang X, Hu G, Betts C, Harmon EY, Keller RS, Van De Water L, Zhou J: Transforming growth factor-beta1-induced transcript 1 protein, a novel marker for smooth muscle contractile phenotype, is regulated by serum response factor/myocardin protein. J Biol Chem 2011, 286(48):41589-41599.
306. Wang YC, Hung HC, Feng CW, Huang SY, Chen CH, Lin YY, Chen YC, Yang SN, Su JH, Sheu JH, Wen ZH: Dihydroaustrasulfone Alcohol (WA-25) Impedes Macrophage Foam Cell Formation by Regulating the Transforming Growth Factor-beta1 Pathway. International journal of Molecular Sciences 2015, 16(5):10507-10525.
307. Akiyama N, Naruse K, Kobayashi Y, Nakamura N, Hamada Y, Nakashima E, Matsubara T, Oiso Y, Nakamura J: High glucose-induced upregulation of Rho/Rho-kinase via platelet-derived growth factor receptor-beta increases migration of aortic smooth muscle cells. Journal of Molecular and Cellular Cardiology 2008, 45(2):326-332.
308. Ishikura K, Fujita H, Hida M, Awazu M: Trapidil inhibits platelet-derived growth factor-induced migration via protein kinase A and RhoA/Rho-associated kinase in rat vascular smooth muscle cells. European Journal of Pharmacology 2005, 515(1-3):28-33.
309. Newby AC: Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates. Cardiovascular Research 2006, 69(3):614-624.
310. Nanni S, Melandri G, Hanemaaijer R, Cervi V, Tomasi L, Altimari A, Van Lent N, Tricoci P, Bacchi L, Branzi A: Matrix metalloproteinases in premature coronary atherosclerosis: influence of inhibitors, inflammation, and genetic polymorphisms. Translational Research : the Journal of Laboratory and Clinical Medicine 2007, 149(3):137-144.
311. Luchtefeld M, Grote K, Grothusen C, Bley S, Bandlow N, Selle T, Struber M, Haverich A, Bavendiek U, Drexler H, Schieffer B: Angiotensin II induces MMP-2 in a p47phox-dependent manner. Biochem Biophys Res Commun 2005, 328(1):183-188.
312. Deatrick KB, Luke CE, Elfline MA, Sood V, Baldwin J, Upchurch GR, Jr., Jaffer FA, Wakefield TW, Henke PK: The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling. J Vasc Surg 2013, 58(5):1375-1384.e1372.
313. Cui Y, Sun YW, Lin HS, Su WM, Fang Y, Zhao Y, Wei XQ, Qin YH, Kohama K, Gao Y: Platelet-derived growth factor-BB induces matrix metalloproteinase-2 expression and rat vascular smooth muscle cell migration via ROCK and ERK/p38 MAPK pathways. Molecular and Cellular Biochemistry 2014, 393(1-2):255-263.
314. Lin SW, Huang SC, Kuo HM, Chen CH, Ma YL, Chu TH, Bee YS, Wang EM, Wu CY, Sung PJ, Wen ZH, Wu DC, Sheu JH, Tai MH: Coral-derived compound WA-25 inhibits angiogenesis by attenuating the VEGF/VEGFR2 signaling pathway. Marine Drugs 2015, 13(2):861-878.