ANGIOTENSIN-II INDUCED MITOGENESIS OF SPONTANEOUSLY HYPERTENSIVE RAT DERIVED CULTURED SMOOTH-MUSCLE CELLS IS DEPENDENT ON AUTOCRINE PRODUCTION OF TRANSFORMING GROWTH-FACTOR-BETA

Angiotensin II (Ang II) has been implicated in the regulation of smoot h muscle cell proliferation after vascular injury, but the molecular m echanisms of this effect remain obscure. The aims of the present study were 1) to determine if Ang II was mitogenic (in a defined serum-free medium) for aortic smooth muscle cells derived from spontaneously hyp ertensive rats, either alone or in combination with epidermal growth f actor, basic fibroblast growth factor, or platelet-derived growth fact or-BB; and 2) to determine if the Ang II effects were mediated by auto crine production of transforming growth factor-beta (TGF-beta). Result s demonstrated that Ang II increased the proliferative response of smo oth muscle cells to epidermal growth factor or platelet-derived growth factor-BB. Ang II alone and in combination with basic fibroblast grow th factor induced a small delayed increase (48-72 hours after treatmen t) in DNA synthesis and [H-3]thymidine labeling indexes without an inc rease in cell number. Ang II effects were at least partially mediated by autocrine production of active TGF-beta in that 1) treatment with A ng II increased TGF-beta activity in conditioned media and 2) TGF-beta neutralizing antibody inhibited Ang II-induced increases in DNA synth esis. However, treatment with exogenous TGF-beta at concentrations ind uced by Ang II failed to elicit a mitogenic response, thus implicating other autocrine factors in mediation of Ang II effects. Results sugge st a potential mechanism whereby Ang II might regulate smooth muscle c ell mitogenesis after vascular injury.