Acute microvascular effects of growth factors

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One potential problem associated with the intravascular administration of VEGF, FGF-2, and other angiogenic growth factors is the periph-

B High-cholesterol diet

B High-cholesterol diet

Fig. 7. Microvascular reactivity studies after 4 wk of vascular endothelial growth factor (VEGF) treatment in a porcine model of myocardial ischemia with (B,C) or without (A) hypercholesterolemia-induced endothelial dysfunction. Graphs show percent relaxation to increasing concentrations of vasodilating agents following preconstriction with U46619. SNP, sodium nitroprusside; ADP, adenosine diphosphate. From ref. 146.

Fig. 7. Microvascular reactivity studies after 4 wk of vascular endothelial growth factor (VEGF) treatment in a porcine model of myocardial ischemia with (B,C) or without (A) hypercholesterolemia-induced endothelial dysfunction. Graphs show percent relaxation to increasing concentrations of vasodilating agents following preconstriction with U46619. SNP, sodium nitroprusside; ADP, adenosine diphosphate. From ref. 146.

Fig. 8. Post- vs prevascular endothelial growth factor (VEGF) treatment ratios of ischemic (left circumflex artery [LCX]) vs nonischemic (left anterior descending artery [LAD]) blood flows in a porcine model of myocardial ischemia with hypercholesterolemia-induced endothelial dysfunction (high-cholesterol diet) compared to controls (normal diet), and the effect of L-arginine supplementation (high-cholesterol + L-arginine). From ref. 146.

Fig. 8. Post- vs prevascular endothelial growth factor (VEGF) treatment ratios of ischemic (left circumflex artery [LCX]) vs nonischemic (left anterior descending artery [LAD]) blood flows in a porcine model of myocardial ischemia with hypercholesterolemia-induced endothelial dysfunction (high-cholesterol diet) compared to controls (normal diet), and the effect of L-arginine supplementation (high-cholesterol + L-arginine). From ref. 146.

eral vasodilation. The angiogenic potential of FGF-2 is largely independent of the release of NO, whereas VEGF-induced vessel formation is potently coupled to the release of NO. The intravascular infusions of FGF-2 and VEGF are poorly tolerated, owing to their vasodilatory effects (115,149) and resulting systemic hypotension. Profound hypotension is obviously not well tolerated by patients with severe and inoperable coronary artery disease. VEGF-induced relaxation may be inhibited by the concomitant administration of l-NAME, suggesting a possible method to counter the vasodilatory effect of acute administration of VEGF. Interestingly, VEGF produces a rapid tachyphylaxis to subsequent bolus injections of the growth factor, and also to the injection of other endothelium-dependent vasoactive agents such as serotonin. The relaxations to sodium nitroprusside and adenosine are not affected, suggesting a selectively acquired defect in the endothelial vasodilatory mechanism (149). Examples of these vascular effects are shown in Fig. 9.

Although the predominant effect of VEGF may lie in the NO-guanylate pathway, other pathways may also be important. Relaxation of vessels by VEGF is not affected to the same degree by the tyrosine kinase inhibitor genistein as it is by an inhibitor of NOS, nor is VEGF-

Fig. 9. Normalization of hypercholesterolemia induced endothelial dysfunction, as measured by endothelial dependent microvascular relaxation, in pigs supplemented chronically with L-arginine. From ref. 145.

induced relaxation totally inhibited by l-NAME (115). This suggests that VEGF-induced relaxation may have an endothelial component independent of NO, or that it may release NO through a mechanism unrelated to its two different tyrosine kinase receptors (149). The VEGF-induced release of platelet-activating factor (PAF), which may cause vasodilation in low concentrations, increases vascular permeability in intact vessels and cultured aortic endothelial cells (150). The cyclooxygenase-2 (COX-2) pathway has also been shown to be upregulated in response to hypoxia as well as exogenous VEGF administration, eventually leading to the synthesis and release of vasodilatory prostanoids (151). An understanding of the acute vascular effects of growth factors may increase our understanding of the initial steps in blood vessel development and growth, and also help clinicians deal with hypotension associated with the intravascular administration of VEGF and other growth factors.

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