RECIPROCAL RELATION BETWEEN VEGF AND NO IN THE REGULATION OF ENDOTHELIAL INTEGRITY

Balloon angioplasty disrupts the protective endothelial lining of the arterial wall, rendering arteries susceptible to thrombosis and intima l thickening. We show here that Vascular endothelial growth factor (VE GF), an endothelial cell mitogen, is upregulated in medial smooth musc le cells of the arterial wall in response to balloon injury. Both prot ein kinase C (PKC) and tyrosine kinase pp60(src) mediate augmented VEG F expression. In contrast, nitric oxide (NO) donors inhibit PKC-induce d VEGF upregulation by interfering with binding of the transcription f actor activator protein-1 (AP-1) to the VEGF promoter. Inhibition of V EGF promoter activation suggests that NO secreted by a restored endoth elium functions as the negative feedback mechanism that downregulates VEGF expression to basal levels. Administration of a neutralizing VEGF antibody impaired reendothelialization following balloon injury perfo rmed in vivo. These findings establish a reciprocal relation between V EGF and NO in the endogenous regulation of endothelial integrity follo wing arterial injury.