ENDOTHELIN-1 AND ANGIOTENSIN-II STIMULATE DELAYED MITOGENESIS IN CULTURED RAT AORTIC SMOOTH-MUSCLE CELLS - EVIDENCE FOR COMMON SIGNALING MECHANISMS

The vasoactive peptides endothelin-1 (ET-1) and angiotensin-II (All) h ave been implicated in chronic hypertension and may play important rol es in related vascular diseases such as restenosis and atherosclerosis . Using a rat aortic smooth muscle (RASM) cell model, both ET-1 and Al l induced concentration-dependent delayed increases in DNA synthesis r elative to that in the serum-deprived controls. Stimulation of DNA syn thesis was maximal at 100 nM for each peptide. All treatment of RASM c ells resulted in a greater mitogenic effect (4- to 7-fold) than that o bserved for ET-1 (3-fold). When added in the presence of All, ET-1 has a supplemental effect on DNA synthesis (5- to 10-fold above control). Although RASM cells expressed both ET(A) and AT(1) receptors, radioli gand binding experiments indicated that approximately 10-fold as many AT(1) receptors as ET(A) receptors were present. In signal transductio n studies, ET-1 and All also elicited concentration-dependent increase s in the intracellular Ca2+ concentration. ET-1 and All also stimulate d phosphoinositide metabolism and phosphorylation of a specific substr ate for protein kinase-C. The release of total inositol phosphates in response to ET-1 and All was concentration dependent and inhibited by the ET(A) receptor-selective antagonist BQ-123 and the AT(1) receptor- selective antagonist losartan, respectively. In addition, tyrosine pho sphorylation of 120- and 75- kilodalton proteins as well as the mitoge n-activated protein-kinase p44(mapk) and p42(mapk) was observed with 5 min of the addition of either ET-1 of All. Taken together, these data indicate that ET-1 and All may promote smooth muscle cell growth thro ugh common intracellular signaling mechanisms.