Reciprocal relation between VEGF and NO in the regulation of endothelial integrity

Abstract

Balloon angioplasty disrupts the protective endothelial lining of the arterial wall, rendering arteries susceptible to thrombosis and intimal thickening. We show here that vascular endothelial growth factor (VEGF), an endothelial cell mitogen, is upregulated in medial smooth muscle cells of the arterial wall in response to balloon injury. Both protein kinase C (PKC) and tyrosine kinase pp60src mediate augmented VEGF expression. In contrast, nitric oxide (NO) donors inhibit PKC-induced VEGF upregulation by interfering with binding of the transcription factor activator protein-1 (AP-1) to the VEGF promoter. Inhibition of VEGF promoter activation suggests that NO secreted by a restored endothelium functions as the negative feedback mechanism that downregulates VEGF expression to basal levels. Administration of a neutralizing VEGF antibody impaired reendothelialization following balloon injury performed in vivo. These findings establish a reciprocal relation between VEGF and NO in the endogenous regulation of endothelial integrity following arterial injury.

Vitamins C and E downregulate vascular VEGF and VEGFR-2 expression in apolipoprotein-E-deficient mice

“…Although the mechanism by which hypercholesterolemia may induce VEGF upregulation in the vessel wall remains unclear, possible pathophysiological stimuli include hypoxia [14], oxidative stress [3] and low NO bioavailability [4]. Moreover, VEGF upregulation has been proposed to be a non-specific stress-induced vascular response in the adult organism [25], or to constitute a vascular homeostatic mechanism for compensating endothelial dysfunction [1].…”

“…Since augmented PKC activity has been shown in apoE−/− [29] and PKC activation can upregulate VEGF expression [4], it is conceivable that the observed in vivo effect of ␣-tocopherol on VEGF expression is due to both antioxidant and PKC inhibitory effects. It could be also argued that differences in the intestinal absorption, translated into different bioavailabilities for ␣ and ␤-tocopherol, could account for the observed effects on VEGF expression.…”

“…It has also been implicated in the maintenance of endothelial integrity, partly through upregulation of endothelial nitric oxide synthase expression [1]. VEGF expression is regulated mainly by hypoxia [2], oxidative stress [3] and nitric oxide [4,5]. The biological effects of VEGF are mediated mainly by two tyrosin kinase receptors: VEGFR-1 (Flt-1) and VEGFR-2 (flk-1/KDR).…”

“…Interestingly, the apoE−/− murine model of hypercholesterolemia is characterized by increased oxidative stress [11] and reduced nitric oxide bioavailability [12], two mechanisms known to contribute to atherosclerotic plaque development and also involved in the regulation of VEGF expression [3,4]. Increased VEGF levels have been reported in plasma from hypercholesterolemic individuals [13] and in coronary arteries from hypercholesterolemic pigs [14].…”

Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer

“…Moreoxer. considerinn, that biolooical activities of VEGF are not merely induction of anaiogenesis (Gabrilovich et al 1996: Tsurumi et al 1997: van der Zee et al 1997 we focused on VEGF mRNA expression itself wxithout study ina the correlation with number of v-essels in the tumour.…”