REGULATION OF VASCULAR ANGIOTENSIN-II RECEPTORS BY EGF

After vascular endothelial injury, angiotensin II (ANG II) plays a rol e in the resulting hypertrophic response, and expression of epidermal growth factor (EGF) is enhanced. Therefore, we tested the possibility that EGF regulates vascular ANG II action and receptor expression. Inc ubation of cultured aortic vascular smooth muscle cells (VSMC) with EG F (or basic fibroblast growth factor but not platelet-derived growth f actor isoforms) resulted in concentration-dependent (1-50 ng/ml EGF), time-dependent (> 8 h), and reversible decreases in ANG II surface rec eptor density. For example, a 50% reduction was observed after exposur e to 50 ng/ml EGF for 24 h. Incubation of cultured VSMC with 50 ng/ml EGF for 24 h resulted in a 77% reduction in ANG II-stimulated inositol phosphate formation. EGF not only prevented but also reversed ANG II receptor upregulation by 100 nM corticosterone. The specific tyrosine kinase inhibitor tyrphostin A48 (50 mu M) reduced EGF-stimulated thymi dine incorporation and EGF-stimulated phosphorylation of mitogen-activ ated protein kinase but did not prevent EGF from reducing ANG II recep tor density. Neither pertussis toxin (100 ng/ml) nor downregulation of protein kinase C by phorbol myristate acetate (100 nM for 24 h) preve nted EGF from reducing ANG; II receptor density. In summary, EGF is a potent negative regulator of vascular ANG II surface receptor density and ANG II action by mechanisms that do not appear to include tyrosine phorphorylation, pertussis toxin-sensitive G proteins, or phorbol est er-sensitive protein kinase C. The possibility that EGF shifts the cel l culture phenotype to one that exhibits reduced surface ANG II densit y cannot be eliminated by the present studies.