Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis

Plaque angiogenesis promotes the growth of atheromas, but the functions of plaque capillaries are not fully determined. Neovascularization may act as a conduit for the entry of leukocytes into sites of chronic inflammation. We observe vasa vasorum density correlates highly with the extent of inflammatory cells, not the size of atheromas in apolipoprotein E-deficient mice. We show atherosclerotic aortas contain activities that promote angiogenesis. The angiogenesis inhibitor angiostatin reduces plaque angiogenesis and inhibits atherosclerosis. Macrophages in the plaque and around vasa vasorum are reduced, but we detect no direct effect of angiostatin on monocytes. After angiogenesis blockade in vivo, the angiogenic potential of atherosclerotic tissue is suppressed. Activated macrophages stimulate angiogenesis that can further recruit inflammatory cells and more angiogenesis. Our findings demonstrate that late-stage inhibition of angiogenesis can interrupt this positive feedback cycle. Inhibition of plaque angiogenesis and the secondary reduction of macrophages may have beneficial effects on plaque stability.

[1]  Lars Holmgren,et al.  Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma , 1994, Cell.

[2]  Shay Soker,et al.  Neuropilin-1 Is Expressed by Endothelial and Tumor Cells as an Isoform-Specific Receptor for Vascular Endothelial Growth Factor , 1998, Cell.

[3]  C. Weyand,et al.  Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant cells. , 1999, The American journal of pathology.

[4]  C. Alpers,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. , 1996, Circulation.

[5]  E. Unanue,et al.  Activated macrophages induce vascular proliferation , 1977, Nature.

[6]  D. Heistad,et al.  Diffusional support of the thoracic aorta in atherosclerotic monkeys. , 1987, Atherosclerosis.

[7]  R. Ross,et al.  Atherosclerosis is an inflammatory disease. , 1998, American heart journal.

[8]  R. Nicosia,et al.  Growth of microvessels in serum-free matrix culture of rat aorta. A quantitative assay of angiogenesis in vitro. , 1990, Laboratory investigation; a journal of technical methods and pathology.

[9]  M. Moses,et al.  HIF-1alpha-mediated up-regulation of vascular endothelial growth factor, independent of basic fibroblast growth factor, is important in the switch to the angiogenic phenotype during early tumorigenesis. , 2001, Cancer research.

[10]  D. Heistad,et al.  Vasa Vasorum in Atherosclerotic Coronary Arteries: Responses to Vasoactive Stimuli and Regression of Atherosclerosis , 1988, Circulation research.

[11]  M A Konerding,et al.  Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. , 1999, Circulation.

[12]  S M Schwartz,et al.  Angiogenesis in human coronary atherosclerotic plaques. , 1994, The American journal of pathology.

[13]  Shigeyoshi Itohara,et al.  Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis , 2000, Nature Cell Biology.

[14]  M. Dake,et al.  Vascular endothelial growth factor enhances atherosclerotic plaque progression , 2001, Nature Medicine.

[15]  M. Davies,et al.  Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. , 1993, British heart journal.

[16]  O. Wiklund,et al.  Evidence of hypoxic areas within the arterial wall in vivo. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[17]  A. Luttun,et al.  Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1 , 2002, Nature Medicine.

[18]  A. Barger,et al.  Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. , 1984, The New England journal of medicine.

[19]  P. Ridker,et al.  C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. , 2000, The New England journal of medicine.

[20]  M. Cybulsky,et al.  A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. , 2001, The Journal of clinical investigation.

[21]  D. Hanahan,et al.  Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. , 1999, Science.

[22]  D. Sane,et al.  Angiostatin binds to smooth muscle cells in the coronary artery and inhibits smooth muscle cell proliferation and migration In vitro. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[23]  R. Nicosia,et al.  Endogenous regulation of angiogenesis in the rat aorta model. Role of vascular endothelial growth factor. , 1997, The American journal of pathology.

[24]  I. Weissman,et al.  Flow cytometric identification of murine neutrophils and monocytes. , 1996, Journal of immunological methods.

[25]  E L Ritman,et al.  Enhanced coronary vasa vasorum neovascularization in experimental hypercholesterolemia. , 1998, The Journal of clinical investigation.

[26]  Claudio Napoli,et al.  Simvastatin Preserves the Structure of Coronary Adventitial Vasa Vasorum in Experimental Hypercholesterolemia Independent of Lipid Lowering , 2002, Circulation.

[27]  P. Libby,et al.  Reduction of atherosclerosis in mice by inhibition of CD40 signalling , 1998, Nature.

[28]  J. Folkman.  Angiogenesis in cancer, vascular, rheumatoid and other disease , 1995, Nature Medicine.

[29]  Ho-Jin Park,et al.  3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Interfere With Angiogenesis by Inhibiting the Geranylgeranylation of RhoA , 2002, Circulation research.

[30]  A. Mantovani,et al.  Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. , 1996, Blood.

[31]  P. Libby,et al.  Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. , 1998, Molecular cell.

[32]  P. Tsao,et al.  Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis , 2001, Nature Medicine.