VASOACTIVE PEPTIDES MODULATE VASCULAR ENDOTHELIAL-CELL GROWTH-FACTOR PRODUCTION AND ENDOTHELIAL-CELL PROLIFERATION AND INVASION

The proliferation of vascular endothelial cells (EC) is an important e vent in angiogenesis, The synthesis of the EC growth factor, vascular endothelial cell growth factor (VEGF), is stimulated by a variety of a ctivators; but the effects of important vasoactive peptides are not we ll understood, and there are no known natural inhibitors of VEGF produ ction, We found that the vasoactive peptides endothelin (ET)-1 and ET- 3 stimulated the synthesis of VEGF protein 3-4-fold in cultured human vascular smooth muscle cells, comparable in magnitude to hypoxia. ET-1 and ET-3 acted through the ETA and ETB receptors, respectively, and s ignaling through protein kinase C was important. Atrial natriuretic pe ptide (ANP), C-type natriuretic peptide, and C-ANP-(4-23), a ligand fo r the natriuretic peptide clearance receptor, equipotently inhibited p roduction of VEGF by as much as 88% and inhibited ET- or hypoxia-stimu lated VEGF transcription, EC proliferation and invasion of matrix were stimulated by VEGF secreted into the medium by ET-incubated vascular smooth muscle cells, This was inhibited by ANP. Our results identify t he natriuretic peptides as the first peptide inhibitors of VEGF synthe sis and indicate a novel mechanism by which vasoactive peptides could modulate angiogenesis.