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ArePlaque angiogenesis and atherosclerosis

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Abstract

Therapeutic angiogenesis trials refer to the stimulation of collateral arterioles and new vascular conduits to perfuse ischemic myocardium and limbs. Atherosclerotic lesions responsible for vascular occlusions themselves are associated with angiogenesis within the vessel wall. Plaque neovascularization is comprised of a network of capillaries that arise from the adventitial vasa vasorum and extend into the intimal layer of atherosclerotic lesions and other types of vascular injury. The functions of these plaque capillaries are proposed to be important regulators of plaque growth and lesion instability. The development of agents that are positive and negative regulators of angiogenesis may have potential therapeutic implications in the progression and acute manifestations of atherosclerosis. This review focuses on the role of plaque angiogenesis in atherosclerosis and discusses the potential therapeutic applications of angiogenesis inhibitors in this disease.

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References and Recommended Reading

  1. Laham RJ, Sellke FW, Edelman ER, et al.: Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, double-blind, placebo-controlled trial. Circulation 1999, 100:1865–1871.

    PubMed  CAS  Google Scholar 

  2. Baumgartner I, Pieczek A, Manor O, et al.: Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia [see comments]. Circulation 1998, 97:1114–1123.

    PubMed  CAS  Google Scholar 

  3. Losordo D, Vale P, Symes J, et al.: Gene therapy for myocardia angiogenesis. Initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 1998, 98:2800–2804.

    PubMed  CAS  Google Scholar 

  4. Schumacher B, Pecher P, von Specht BU, Stegmann T: Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease [see comments]. Circulation 1998, 97:645–650.

    PubMed  CAS  Google Scholar 

  5. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators [see comments] [published erratum appears in N Engl J Med 1997, Jan 9;336:147]. N Engl J Med 1996, 335:217–225.

    Article  Google Scholar 

  6. Asahara T, Chen D, Takahashi T, et al.: Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization [see comments]. Circ Res 1998, 83:233–240.

    PubMed  CAS  Google Scholar 

  7. Shyu KG, Manor O, Magner O, et al.: Direct intramuscular injection of plasmid DNA encoding angiopoietin-1 but not angiopoietin-2 augments revascularization in the rabbit ischemic hindlimb. Circulation 1998, 98:2081–2087.

    PubMed  CAS  Google Scholar 

  8. Roberts WC, Virmani R: Formation of new coronary arteries within a previously obstructed epicardial coronary artery (intraarterial arteries): a mechanism for occurrence of angiographically normal coronary arteries after healing of acute myocardial infarction. Am J Cardiol 1984, 54:1361–1362.

    Article  PubMed  CAS  Google Scholar 

  9. Ware JA, Simons M: Angiogenesis in ischemic heart disease. Nat Med 1997, 3:158–164.

    Article  PubMed  CAS  Google Scholar 

  10. Van Belle E, Rivard A, Chen D, et al.: Hypercholesterolemia attenuates angiogenesis but does not preclude augmentation by angiogenic cytokines. Circulation 1997, 96:2667–2674.

    PubMed  Google Scholar 

  11. Rivard A, Fabre JE, Silver M, et al.: Age-dependent impairment of angiogenesis. Circulation 1999, 99:111–120.

    PubMed  CAS  Google Scholar 

  12. Rivard A, Silver M, Chen D, et al.: Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am J Pathol 1999, 154:355–363.

    PubMed  CAS  Google Scholar 

  13. Arras M, Ito WD, Scholz D, et al.: Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 1998, 101:40–50.

    PubMed  CAS  Google Scholar 

  14. Barger AC, Beeuwkes RD, Lainey LL, Silverman KJ: Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med 1984, 310:175–177.

    Article  PubMed  CAS  Google Scholar 

  15. Koester W: Endarteritis and arteritis. Berl Klin Wochenschr 1876, 13:454–455.

    Google Scholar 

  16. Zhang Y, Cliff WJ, Schoefl GI, Higgins G: Immunohistochemical study of intimal microvessels in coronary atherosclerosis. Am J Pathol 1993, 143:164–172.

    PubMed  CAS  Google Scholar 

  17. Kwon HM, Sangiorgi G, Ritman EL, et al.: Enhanced coronary vasa vasorum neovascularization in experimental hypercholesterolemia. J Clin Invest 1998, 101:1551–1556.

    PubMed  CAS  Google Scholar 

  18. Auerbach R, Sidky YA: Nature of the stimulus leading to lymphocyte-induced angiogenesis. J Immunol 1979, 123:751–754.

    PubMed  CAS  Google Scholar 

  19. Kaartinen M, Penttila A, Kovanen PT: Mast cells accompany microvessels in human coronary atheromas: implications for intimal neovascularization and hemorrhage. Atherosclerosis 1996, 123:123–131.

    Article  PubMed  CAS  Google Scholar 

  20. Polverini PJ, Cotran RS, Gimbrone Jr, MA, Unanue ER: Activated macrophages induce vascular proliferation. Nature 1977, 269:804–806.

    Article  PubMed  CAS  Google Scholar 

  21. O’Brien KD, McDonald TO, Chait A, et al.: Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation 1996, 93:672–682.

    PubMed  CAS  Google Scholar 

  22. O’Brien ER, Garvin MR, Dev R, et al.: Angiogenesis in human coronary atherosclerotic plaques. Am J Pathol 1994, 145:883–894.

    PubMed  CAS  Google Scholar 

  23. Engerman RL, Pfaffenbach D, Davis MD: Cell turnover of capillaries. Lab Invest 1967, 17:738–743.

    PubMed  CAS  Google Scholar 

  24. Wolinsky H, Glagov S: A lamellar unit of aortic medial structure and function in mammals. Circ Res 1967, 20:99–111.

    PubMed  CAS  Google Scholar 

  25. Geiringer E: Intimal vascularization and atherosclerosis. J Pathol Bacteriol 1951, 63:210–211.

    Article  Google Scholar 

  26. Moulton KS, Heller E, Konerding MA, et al.: Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice [see comments]. Circulation 1999, 99:1726–1732.

    PubMed  CAS  Google Scholar 

  27. Williams JK, Armstrong ML, Heistad DD: Vasa vasorum in atherosclerotic coronary arteries: responses to vasoactive stimuli and regression of atherosclerosis. Circ Res 1988, 62:515–523.

    PubMed  CAS  Google Scholar 

  28. Brogi E, Winkles JA, Underwood R, et al.: Distinct patterns of expression of fibroblast growth factors and their receptors in human atheroma and nonatherosclerotic arteries. Association of acidic FGF with plaque microvessels and macrophages. Journal of Clinical Investigation 1993, 92:2408–2418.

    PubMed  CAS  Google Scholar 

  29. Couffinhal T, Kearney M, Witzenbichler B, et al.: Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in normal and atherosclerotic human arteries. Am J Pathol 1997, 150:1673–1685.

    PubMed  CAS  Google Scholar 

  30. Inoue M, Itoh H, Ueda MT, et al.: Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation 1998, 98:2108–2116.

    PubMed  CAS  Google Scholar 

  31. Kuzuya M, Satake S, Esaki T, et al.: Induction of angiogenesis by smooth muscle cell-derived factor: possible role in neovascularization in atherosclerotic plaque. J Cellular Physiol 1995, 164:658–667.

    Article  CAS  Google Scholar 

  32. Bo WJ, Mercuri M, Tucker R, Bond MG: The human carotid atherosclerotic plaque stimulates angiogenesis on the chick chorioallantoic membrane. Atherosclerosis 1992, 94:71–78.

    Article  PubMed  CAS  Google Scholar 

  33. Roth JJ, Gahtan V, Brown JL, et al.: Thrombospondin-1 is elevated with both intimal hyperplasia and hypercholesterolemia. J Surg Res 1998, 74:11–16.

    Article  PubMed  CAS  Google Scholar 

  34. Good DJ, Polverini PJ, Rastinejad F, et al.: A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci U S A 1990, 87:6624–6628.

    Article  PubMed  CAS  Google Scholar 

  35. Chen D, Asahara T, Krasinski K, et al.: Antibody blockade of thrombospondin accelerates reendothelialization and reduces neointima formation in balloon-injured rat carotid artery [see comments]. Circulation 1999, 100:849–854.

    PubMed  CAS  Google Scholar 

  36. Miosge N, Sasaki T, Timpl R: Angiogenesis inhibitor endostatin is a distinct component of elastic fibers in vessel walls. FASEB J 1999, 13:1743–1750.

    PubMed  CAS  Google Scholar 

  37. Falk E, Shah PK, Fuster V: Coronary plaque disruption. Circulation 1995, 92:657–671.

    PubMed  CAS  Google Scholar 

  38. Paterson JC: Capillary rupture with intimal hemorrhage as a causative factor in coronary thrombosis. Arch Pathol 1938, 25:474–487.

    Google Scholar 

  39. Tenaglia AN, Peters KG, Sketch Jr MH, Annex BH: Neovascularization in atherectomy specimens from patients with unstable angina: implications for pathogenesis of unstable angina. Am Heart J 1998, 135:10–14.

    Article  PubMed  CAS  Google Scholar 

  40. Burke AP, Farb A, Malcom GT, et al.: Coronary risk factors and plaque morphology in men with coronary disease who died suddenly [see comments]. N Engl J Med 1997, 336:1276–1282.

    Article  PubMed  CAS  Google Scholar 

  41. Barger AC, Beeuwkes RD: Rupture of coronary vasa vasorum as a trigger of acute myocardial infarction. Am J Cardiol 1990, 66:41G-43G.

    Article  PubMed  CAS  Google Scholar 

  42. Davies MJ, Thomas AC: Plaque fissuring--the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J 1985, 53:363–373.

    PubMed  CAS  Google Scholar 

  43. van der Wal AC, Becker AE, van der Loos CM, Das PK: Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology [see comments]. Circulation. 1994, 89:36–44.

    PubMed  Google Scholar 

  44. Libby P: Molecular bases of the acute coronary syndromes. Circulation 1995, 91:2844–2850.

    PubMed  CAS  Google Scholar 

  45. Kumamoto M, Nakashima Y, Sueishi K: Intimal neovascularization in human coronary atherosclerosis: its origin and pathophysiological significance. Human Pathology 1995, 26:450–456.

    Article  PubMed  CAS  Google Scholar 

  46. Virmani R, Roberts WC: Extravasated erythrocytes, iron, and fibrin in atherosclerotic plaques of coronary arteries in fatal coronary heart disease and their relation to luminal thrombus: frequency and significance in 57 necropsy patients and in 2958 five mm segments of 224 major epicardial coronary arteries. Am Heart J 1983, 105:788–797.

    Article  PubMed  CAS  Google Scholar 

  47. Brooks PC, Stromblad S, Sanders LC, et al.: Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 1996, 85:683–693.

    Article  PubMed  CAS  Google Scholar 

  48. Gross JL, Moscatelli D, Rifkin DB: Increased capillary endothelial cell protease activity in response to angiogenic stimuli in vitro. Proc Natl Acad Sci U S A 1983, 80:2623–2627.

    Article  PubMed  CAS  Google Scholar 

  49. Hiraoka N, Allen E, Apel I, et al.: Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell 1998, 95:365–377.

    Article  PubMed  CAS  Google Scholar 

  50. Galis ZS, Sukhova GK, Lark MW, Libby P: Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994, 94:2493–2503.

    PubMed  CAS  Google Scholar 

  51. Davies MJ, Richardson PD, Woolf N, et al.: Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J 1993, 69:377–381.

    PubMed  CAS  Google Scholar 

  52. Goldstein JA, Demetriou D, Grines CL, et al.: Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000, 343:915–922.

    Article  PubMed  CAS  Google Scholar 

  53. Aikawa M, Rabkin E, Okada Y, et al.: Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma. A potential mechanism of lesion stabilization. Circulation 1998, 97:2433–2444.

    PubMed  CAS  Google Scholar 

  54. Jones MK, Wang H, Peskar BM, et al.: Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing [see comments]. Nat Med 1999, 5:1418–1423.

    Article  PubMed  CAS  Google Scholar 

  55. Katori M, Majima M, Harada Y: Possible background mechanisms of the effectiveness of cyclooxygenase-2 inhibitors in the treatment of rheumatoid arthritis. Inflammation Res 1998, 47:S107–111.

    Article  CAS  Google Scholar 

  56. Shiff SJ, Rigas B: Aspirin for cancer [news; comment]. Nat Med 1999, 5:1348–1349.

    Article  PubMed  CAS  Google Scholar 

  57. Williams JK, Sukhova GK, Herrington DM, Libby P: Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Am Coll Cardiol 1998, 31:684–691.

    Article  PubMed  CAS  Google Scholar 

  58. Rafii S: Circulating endothelial precursors: mystery, reality, and promise [comment]. J Clin Invest 2000, 105:17–19.

    Article  PubMed  CAS  Google Scholar 

  59. Barleon B, Sozzani S, Zhou D, et al.: Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 1996, 87:3336–3343.

    PubMed  CAS  Google Scholar 

  60. Thurston G, Rudge JS, Ioffe E, et al.: Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 2000, 6:460–463.

    Article  PubMed  CAS  Google Scholar 

  61. Couffinhal T, Silver M, Zheng LP, et al.: Mouse model of angiogenesis. Am J Pathol 1998, 152:1667–1679.

    PubMed  CAS  Google Scholar 

  62. D’Amato RJ, Loughnan MS, Flynn E, Folkman J: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994, 91:4082–4085.

    Article  PubMed  CAS  Google Scholar 

  63. Tamura F, Vogelsang GB, Reitz BA, et al.: Combination thalidomide and cyclosporine for cardiac allograft rejection. Comparison with combination methylprednisolone and cyclosporine. Transplantation 1990, 49:20–25.

    Article  PubMed  CAS  Google Scholar 

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  1. Cardiovascular Division, Brigham and Women’s Hospital, and Surgical Research, Children’s Hospital, 300 Longwood Avenue, Enders 10, 02115, Boston, MA, USA

    Karen S. Moulton MD

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Moulton, K.S. ArePlaque angiogenesis and atherosclerosis. Curr Atheroscler Rep 3, 225–233 (2001). https://doi.org/10.1007/s11883-001-0065-0

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