ANGIOTENSIN-CONVERTING ENZYME-INHIBITION ABOLISHES MEDIAL SMOOTH-MUSCLE PDGF-AB BIOSYNTHESIS AND ATTENUATES CELL-PROLIFERATION IN INJURED CAROTID ARTERIES - RELATIONSHIPS TO NEOINTIMA FORMATION

Background ACE inhibitors can attenuate the development of intimal fib rocellular lesions after balloon catheter vessel injury, but the mecha nisms responsible are unknown. Methods and Results To evaluate how bas ic fibroblast growth factor (FGF-2) and the platelet-derived growth fa ctor (PDGF) isoforms are affected by ACE inhibition in injured rat car otid arteries in relation to smooth muscle cell (SMC) proliferation, w e examined the effects of oral perindopril on FGF-2 and PDGF isoform l evels in carotid arteries 2 days after balloon catheter injury. [H-3]T hymidine incorporation into medial and intimal SMCs was also assessed. Uninjured vessels contained two forms of FGF-2, with molecular weight s of 18 and 22 kD, and PDGF-AA. Two days after injury, FGF-2 and PDGF- AA levels were markedly reduced, but high levels of PDGF-AB became app arent when the SMCs were proliferating. Perindopril completely abolish ed the biosynthesis of PDGF-AB but had little effect on residual FGF-2 . This was accompanied by a 25% reduction in medial SMC proliferation. Neointimal cell proliferation 10 days after injury was unaffected by perindopril, although neointima size was reduced by 30%. Commencing pe rindopril treatment 4 days after the injury confirmed that early event s associated with effects on medial SMCs were the major contributors t o the attenuated neointimal lesions. Conclusions The ability of ACE in hibitors such as perindopril to attenuate neointima formation and grow th in balloon catheter-injured rat carotid arteries is dependent on ea rly events in the media, the inhibition of SMC PDGF-AB biosynthesis an d attenuation of proliferation. Neointima formation in similarly injur ed vessels containing SMCs that are either unresponsive to PDGF-AB or exhibit an ACE-independent profile of growth factor biosynthesis respo nses may account for the ineffectiveness of ACE inhibition in some spe cies.