Mechanisms of Angiogenesis

Angiogenesis occurs by the budding of new blood vessels from existing vessels (Fig. 44-1). Inflammation and hypoxia are the two major stimuli for new vessel growth. Hypoxia regulates angiogenesis predominantly by activating a transcription factor, hypoxia-inducible factor-1, which in turn activates the angiogenesis gene expression cascade. Inflammation stimulates angiogenesis mainly by the secretion of inflammatory cytokines derived primarily from macrophages. In either event, the result is production of vascular endothelial growth factor (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 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.

Figure 44-1 Mechanisms of angiogenesis.

bFGF, basic fibroblast growth factor; HIF-1, hypoxia inducible factor; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor.

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; in fact, the cardiovascular system is the first organ system to function during embryogenesis. In adult females, the menstrual cycle is dependent on cyclic angiogenesis that is stimulated in part by reproductive hormones. Beyond this, however, most angiogenesis in adults occurs in pathologic 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, as 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 media of blood vessels remains avascular until a critical width is achieved, beyond which vascularization is necessary for medial nutrition. 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. 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.

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