In all these cases, the invading endothelial cells respond to signals produced by the tissue that they invade. The signals are complex, but a key part is played by vascular endothelial growth factor (VEGF). The regulation of blood vessel growth to match the needs of the tissue depends on the control of VEGF production, through changes in the stability of its mRNA and in its rate of transcription. The latter control is relatively well understood. A shortage of oxygen, in practically any type of cell, causes an increase in the intracellular level of a transcription factor called hypoxia-inducible factor 1α (HIF1α). HIF1α stimulates transcription of Vegf (and of other genes whose products are needed when oxygen is in short supply). The VEGF protein is secreted, diffuses through the tissue, and acts on nearby endothelial cells, stimulating them to proliferate, to produce proteases to help them digest their way through the basal lamina of the parent capillary or venule, and to form sprouts. The tip cells of the sprouts detect the VEGF gradient and move toward its source. As the new vessels form, bringing blood to the tissue, the oxygen concentration rises. The HIF1α activity then declines, VEGF production is shut off, and angiogenesis comes to a halt (Figure 22–26).
Figure 22–25 New capillary formation in response to wounding. Scanning electron micrographs of casts of the system of blood vessels surrounding the margin of the cornea show the reaction to wounding. the casts are made by injecting a resin into the vessels and letting the resin set; this reveals the shape of the lumen, as opposed to the shape of the cells. Sixty hours after wounding, many new capillaries have begun to sprout toward the site of injury, which is just above the top of the picture. their oriented outgrowth reflects a chemotactic response of the endothelial cells to an angiogenic factor released at the wound. (Courtesy of peter C. burger.)
Figure 22–26 The regulatory mechanism controlling blood vessel growth according to a tissue’s need for oxygen.
lack of oxygen triggers the secretion of veGF, which stimulates angiogenesis.
Signals from endothelial Cells Control Recruitment of pericytes and Smooth muscle Cells to Form the vessel wall
The vascular network is continually remodeled as it grows and adapts. A newly formed vessel may enlarge; or it may sprout side branches; or it may regress. Smooth muscle and other connective-tissue cells that pack themselves around the endothelium (see Figure 22–23) help to stabilize vessels as they enlarge. This process of vessel wall formation begins with recruitment of pericytes. Small numbers of these cells travel outward in company with the stalk cells of each endothelial sprout. The recruitment and proliferation of pericytes and smooth muscle cells to form a vessel wall depend on platelet-derived growth factor-B (PDGF-B) secreted by the endothelial cells and on PDGF receptors in the pericytes and smooth muscle cells. In mutants lacking this signal protein or its receptor, these vessel wall cells are missing in many regions. As a result, the embryonic blood vessels develop microaneurysms—microscopic pathological dilatations—that eventually rupture, as well as other abnormalities, reflecting the importance of signals exchanged in both directions between the exterior cells of the wall and the endothelial cells.