FIBROBLAST GROWTH-FACTOR STIMULATES ANGIOTENSIN-CONVERTING ENZYME EXPRESSION IN VASCULAR SMOOTH-MUSCLE CELLS - POSSIBLE MEDIATOR OF THE RESPONSE TO VASCULAR INJURY

Angiotensin converting enzyme (ACE) activity contributes to the vascul ar response to injury because ACE inhibition limits neointima formatio n in rat carotid arteries after balloon injury. To investigate the mec hanisms by which ACE may contribute to vascular smooth muscle cell (VS MC) proliferation, we studied expression of ACE in vivo after injury a nd in vitro after growth factor stimulation. ACE activity 14 d after i njury was increased 3.6-fold in the injured vessel. ACE expression, me asured by immunohistochemistry, became apparent at 7 d in the neointim a and at 14 d was primarily in the most luminal neointimal cells. To c haracterize hormones that induce ACE in vivo, cultured VSMC were expos ed to steroids and growth factors. Among steroids, only glucocorticoid s stimulated ACE expression with an 8.0+/-2.1-fold increase in activit y and a 6.5-fold increase in mRNA (30 nM dexamethasone for 72 h). Amon g growth factors tested, only fibroblast growth factor (FGF) stimulate d ACE expression (4.2+/-0.7-fold increase in activity and 1.6-fold inc rease in mRNA in response to 10 ng/ml FGF for 24 h). Dexamethasone and FGF were synergistic at the indicated concentrations inducing 50.6+/- 12.4-fold and 32.5-fold increases in activity and mRNA expression, res pectively. In addition, when porcine iliac arteries were transfected w ith recombinant FGF-1 (in the absence of injury), ACE expression incre ased in neointimal VSMC, to the same extent as injured, nontransfected arteries. The data suggest a temporal sequence for the response to in jury in which FGF induces ACE, ACE generates angiotensin II, and angio tensin II stimulates VSMC growth in concert with FGF.