Abstract
From a clinical perspective, the contribution of pathologic angiogenesis to the development of high-risk plaques is substantial, since the immature 'leaky' vasa vasorum (Vv) are considered a primary source of intraplaque hemorrhage. The occurrence of hemorrhagic events is beginning to emerge as a leading factor contributing to necrotic core expansion in late plaques based on accumulated erythrocyte-derived cholesterol and complications of secondary inflammation. Therefore, a further understanding of neovascularization of coronary atheroma may impact new treatment strategies targeted at plaque stabilization. While the Vv of normal arteries represents a quiescent, but functional microvascular network localized to the adventitia, atherosclerotic plaques express a latent proangiogenic phenotype represented by invading adventitial vasa vasorum (Vv). The development of intraplaque Vv represents a complex process supported by a multitude of factors involving endothelial proliferation and migration and a microenvironment enriched in growth factors, inflammatory cells, and extracellular matrix proteases. Initiating factors of angiogenesis constitute a physiologic response strongly driven by molecular signals triggered by hypoxia along with a positive association with hypercholesterolemia. The development of necrosis however, in complicated plaques, further provides a chronic inflammatory milieu consisting of a wide array of infiltrating immune cells and their secretory cytokines, chemokines, and growth factors in addition to bioactive lipid oxidation products. Moreover, immune activators also produce many proteases, ranging from urokinase Plasminogen Activator (uPA) to a variety of matrix metalloproteinases, to help degrade the basement membrane thereby facilitating the directional invasion of microvessels from the adventitia. Finally, restoring the balance of pro- and anti-angiogenic factors in plaques to that of a 'normalized' physiologic setting may provide a therapeutic strategy thereby reducing or eliminating intraplaque hemorrhage. The mechanisms of how a lipid rich inflammatory microenvironment contributes to the development of plaque angiogenesis will be a crucial step for furthering an understanding of plaque biology as well as for developing innovative approaches for treating atherosclerosis ahead of current lipid lowering therapies and stents.
Original language | English |
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Title of host publication | Therapeutic Angiogenesis for Vascular Diseases |
Subtitle of host publication | Molecular Mechanisms and Targeted Clinical Approaches for the Treatment of Angiogenic Disease |
Publisher | Springer Netherlands |
Pages | 213-236 |
Number of pages | 24 |
ISBN (Print) | 9789048194940 |
DOIs | |
State | Published - 2011 |
Externally published | Yes |
Keywords
- Angiogenesis
- Atherosclerosis
- Plaque rupture
- Vasa vasorum
- Vascular normalization