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Angiogenesis and Atherosclerosis
Revascularization via coronary artery bypass surgery and percutaneous coronary intervention (PCI) remains the definitive therapy for patients with refractory ischemic heart disease, particularly when accompanied by left ventricular (LV) dysfunction. In particular, bypass surgery reduces mortality in patients with multivessel coronary artery disease and LV dysfunction. However, the surgery itself is invasive and is associated with significant mortality and morbidity. In fact, 37% of patients who undergo surgery are found to have one or more coronary vessels that are not technically suitable for bypass grafting. In addition, many patients are poor candidates for bypass based on their coronary anatomy, coexisting conditions, or the severity of their heart failure. Likewise, anatomic complications may make PCI (e.g., balloon angioplasty and stent implantation) a poor choice for many of these patients. Up to 10% to 30% of patients with angina pectoris and obstructive coronary artery disease who undergo cardiac catheterization cannot be treated with either coronary artery bypass or PCI due to diffuse obstructive coronary artery disease. Therefore there is a substantial need for an alternative means of revascularization. The identification of endogenous pathways that regulate angiogenesis—the growth of new blood vessels from existing vessels—has fostered the intriguing hypothesis that if angiogenesis could be promoted in a controlled manner, endogenous pathways could be stimulated to augment blood vessel formation and revascularize tissues in myocardial ischemic zones.
Mechanisms of Angiogenesis
Angiogenesis occurs by the budding of new blood vessels from existing vessels ( Fig. 14.1 ). Inflammation and hypoxia are the two major stimuli for new vessel growth. Hypoxia regulates angiogenesis predominantly by activating transcription factors, hypoxia-inducible factors (HIF) 1 and 2, which, in turn, activate the angiogenesis gene expression cascades, including vascular endothelial growth factor (VEGF), platelet growth factor, angiopoietin 1 and 2, as well as stromal cell-derived factor 1α. Based on this concept, HIF-1 promotes sprouting of blood vessels and neovascularization by homing of stem cells and enhancing vascular endothelial cell proliferation. HIF-2 mediates vascular maintenance. Inflammation stimulates angiogenesis mainly by the secretion of inflammatory cytokines derived primarily from macrophages. In either of these events, the result is production of VEGF and other potent angiogenic peptides. VEGF interacts with specific receptors on endothelial cells that, in turn, activate pathways to break down the extracellular matrix and stimulate proliferation and migration toward an angiogenic stimulus and recruitment of stem cells, pericytes, and smooth muscle cells to establish the three-dimensional structure of a blood vessel. After making appropriate connections with the vascular system, the newly formed vessel is capable of maintaining blood flow and providing oxygen to the tissue in need.
Angiogenesis occurs in numerous circumstances, some of which are necessary for normal development and organ function. In other circumstances, angiogenesis is a maladaptive response to local injury or stress. During development, the formation of every organ system is dependent on angiogenic events; the cardiovascular system is the first organ system to function during embryogenesis. In women, the menstrual cycle is dependent on cyclic angiogenesis that is stimulated in part by reproductive hormones. However, most angiogenesis in adults occurs in pathological conditions or as a response to injury. Tumor growth and metastasis, diabetic vascular disease (including retinopathy), inflammatory arthritides, and wound healing are some of the processes that depend on angiogenesis. In addition, the invasion of ischemic tissues with new capillaries and the development of a collateral circulation to supply occluded vessels, which may occur in chronic obstructive coronary disease, are angiogenic processes.
Angiogenesis and Atherosclerosis
The response to ischemia in organs such as the heart involves angiogenic events that increase perfusion to the compromised tissue. Thus it is ironic that atherosclerosis (the most common cause of myocardial ischemia) is itself an angiogenesis-dependent process. The possibility that neovascularization contributes to the pathophysiology of atherosclerosis surfaced when cinefluorography demonstrated the presence of rich networks of vessels surrounding human atherosclerotic plaques. Diffusion of oxygen and other nutrients is limited to 100 µm from the lumen of the blood vessel and is adequate to nourish the inner media and intimal layers in normal arteries. The media of arteries remains avascular until a critical width is achieved, beyond which vascularization is necessary for medial nutrition. As vessel wall thickness increases in the setting of vascular disease, proliferation of the vasa vasorum and intimal neovascularization is observed. Increased blood flow within atherosclerotic lesions is due to new growth of medial vessels and not to dilation of existing vessels. New vessels in atherosclerotic lesions form primarily by branching from the adventitial vasa vasorum.
Neovascularization may contribute to the clinical consequences of atherosclerosis by several mechanisms. Neovascularization provides a source of nutrients, growth factors, and vasoactive molecules to cells within the media and the neointima, which is evident from the association between neovascularization of atherosclerotic lesions and proliferation of adjacent smooth muscle cells. Intimal hemorrhage, which is associated with plaque instability, is due to rupture of the rich network of friable new capillaries surrounding lesions. Regulation of blood flow through plaque microvessels may contribute to the pathophysiology of vasospasm in advanced lesions. Vascular wall remodeling also seems to be related to neovascularization. Finally, neovascularization within human atherosclerotic lesions is associated with expression of adhesion molecules, which is strongly related to neointimal inflammatory cell recruitment. Increasingly, accumulating histopathological data have associated plaque angiogenesis with more rapidly progressive and unstable vascular disease. Microvessel density is greatest in vulnerable atheroma plaques characterized with marked macrophage infiltration of the fibrous cap, thin cap, and large lipid-rich core. The presence of angiogenesis at the base of the plaque has been independently correlated with plaque rupture, underscoring the potential for a direct contributory role of neovascularization in this process. Antiangiogenesis therapy is understandably an attractive concept that targets inhibition of microvessel formation and/or function within atherosclerotic plaque. Although >300 angiogenesis inhibitors have been identified and >80 are being tested in clinical studies for cancer therapy, the greatest concern regarding the use of angiogenesis inhibitors to treat atherosclerosis is the potential aggravation of preexisting myocardial ischemia caused by inhibition of beneficial angiogenesis in the setting of ischemic heart disease.
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