The New Blood Vessels Induced by VEGFA

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VEGF-A, and particularly its 164/5 isoform, is thought to be the most important mediator of pathological angiogene-sis, including that induced by tumors, wounds, and inflammation. However, all of these complex entities involve the activities of multiple cytokines. Recently, it has been possible to tease apart those aspects of the angiogenic response that are attributable solely to VEGF-A by expressing VEGF-A164 in an adenoviral vector (Ad-VEGF-A164). Upon introduction into mouse tissues, infected host cells express VEGF-A164 protein within a few hours and continue to secrete it at fairly constant levels for approximately two weeks. VEGF-A164 induces a highly reproducible, time-ordered sequence of events that is qualitatively similar in all tissues studied. Local microvessels become hyperpermeable to plasma proteins, resulting in tissue edema and deposition of extravascular fibrin. By 18 hours, enlarged, thin-walled, pericyte-poor, hyperpermeable, and strongly VEGF receptor-positive "mother" vessels develop from preexisting venules (Figure 4). Such mother vessels are characteristic of many tumors, healing wounds, and so forth and form according to a three-step process: (1) proteolytic degradation of the noncompliant (nonelastic) vascular basement membrane; (2) detachment of pericytes from basement membrane; and (3) transfer of VVO membranes to the

Glomeruloid Vessels

Figure 4 Schematic diagram summarizing the progression of the angiogenic response that follows introduction of a VEGF-A164-expressing adenoviral vector in vivo. Mother vessels develop and may evolve into glomeruloid bodies, vascular malformations, and daughter capillaries. Finally, as VEGF-A164 expression wanes, glomeruloid bodies undergo apopto-sis, whereas malformations achieve VEGF-A independence and persist indefinitely. [Republished in modified form from Pettersson et al. (2000), Laboratory Investigation 80, 99]. (see color insert)

Figure 4 Schematic diagram summarizing the progression of the angiogenic response that follows introduction of a VEGF-A164-expressing adenoviral vector in vivo. Mother vessels develop and may evolve into glomeruloid bodies, vascular malformations, and daughter capillaries. Finally, as VEGF-A164 expression wanes, glomeruloid bodies undergo apopto-sis, whereas malformations achieve VEGF-A independence and persist indefinitely. [Republished in modified form from Pettersson et al. (2000), Laboratory Investigation 80, 99]. (see color insert)

plasma membrane, allowing endothelial cells to thin and spread over the enlarged surface area that was made possible by basement membrane degradation.

Mother vessels are transitional structures that generally persist as such for only a few days (Figure 4). They may divide into smaller channels by projecting transluminal endothelial cell "bridges" into and across mother vessel lumens; these divide blood flow into smaller channels that separate from each other over time, forming individual smaller-caliber "daughter" capillaries. Mother vessels also evolve to form glomeruloid bodies, poorly organized conglomerates of endothelial cells and pericytes that are also found in tumors such as glioblastoma multiforme. Other mother vessels acquire a coating of smooth muscle cells and/or fibrosis and take on the appearance of arteriovenous vascular malformations. Taken together, these findings show that VEGF-A is sufficient to generate the mother vessels, glomeruloid bodies, and vascular malformations found in various human pathologies.

In addition, VEGF-A164 is also able to induce a modest degree of arteriogenesis and to generate abnormal "giant" lymphatics that are characterized by very large size and poor function. Lymphatics of this description occur in patients with Crohn's disease and in lymphangiomas (lymphatic malformations).

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Essentials of Human Physiology

Essentials of Human Physiology

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