Angiogenesis

Angiogenesis (the formation of new vessels from resident capillaries) involves distinct stages: matrix degradation, migration, proliferation, and organization of endothelial cells (ECs) into tubes (Figure 1). An increase in vascular permeability is one of the earliest steps in the process. ECs dissociate themselves from surrounding tissue by secreting enzymes that degrade extracellular matrix (basement membrane). Simultaneously, ECs replicate and align themselves into "tubules," a process described as sprouting (Figure 1). EC proliferation and migration will then continue and the sprout continues to forge its way through matrix proteins ever elongating and increasing in lumenal size. This it achieves by dissolving matrix components. The cells ultimately anastomose to existing vessels, which reestablishes blood flow through the newly formed vessel and therefore restores oxygenation of the compromised tissue. Maturation and stabilization of the new vessels occur through the recruitment of pericytes and vascular smooth muscle cells (VSMC).

Figure 1 Principal steps in microvascular repair: angiogenesis. (1) Trauma following wounding or surgery disrupts normal blood flow, elicits the formation of a thrombus and the accumulation of platelet neutrophils, monocytes, and immune cells, and renders tissue hypoxic. Release substances from these bloods cells and thrombus components, coupled with hypoxia, trigger the expression of angiogenic factors including VEGF, angiopoietins, and HIF-1 a. (2) Endothelial cells (ECs) take on a migratory and replicative phenotype and detach from the matrix by secretion of matrix proteases. (3) ECs continue to replicate and migrate simultaneously aligning themselves to form tubules (sprouting). (4) The new microvessel (MV) grows in the direction of an oxygen gradient toward a capillary that carries red blood cells. MVs can release chemotactic substances that promote pericytes to migrate and associate with the MV. (5) The new MV (bio)anastomoses with an intact neighboring capillary restoring blood supply to the tissue. The subsequent intrinsic flow imparts longevity to the MVs and adapts functionally according to the needs of the tissue it supplies. (see color insert)

Figure 1 Principal steps in microvascular repair: angiogenesis. (1) Trauma following wounding or surgery disrupts normal blood flow, elicits the formation of a thrombus and the accumulation of platelet neutrophils, monocytes, and immune cells, and renders tissue hypoxic. Release substances from these bloods cells and thrombus components, coupled with hypoxia, trigger the expression of angiogenic factors including VEGF, angiopoietins, and HIF-1 a. (2) Endothelial cells (ECs) take on a migratory and replicative phenotype and detach from the matrix by secretion of matrix proteases. (3) ECs continue to replicate and migrate simultaneously aligning themselves to form tubules (sprouting). (4) The new microvessel (MV) grows in the direction of an oxygen gradient toward a capillary that carries red blood cells. MVs can release chemotactic substances that promote pericytes to migrate and associate with the MV. (5) The new MV (bio)anastomoses with an intact neighboring capillary restoring blood supply to the tissue. The subsequent intrinsic flow imparts longevity to the MVs and adapts functionally according to the needs of the tissue it supplies. (see color insert)

Angiogenesis under normal conditions is self-limiting so that when sufficient vessel formation has occurred to satisfy the oxygen demands of the tissue, the endothelial cells become quiescent and the vessels either remain or regress if they are not needed. Apoptosis plays a central role in regression or cessation of angiogenesis. Once a microvessel has formed it becomes stable in that ECs become resistant to exogenous factors (i.e., quiescent) and survive for years. Newly formed microvessels, of course, adopt the prerequisite properties required for the normal function of any given tissue.

The mechanisms underlying this process are expanded upon in the following.

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