VASOACTIVE SUBSTANCES REGULATE VASCULAR SMOOTH-MUSCLE CELL APOPTOSIS - COUNTERVAILING INFLUENCES OF NITRIC-OXIDE AND ANGIOTENSIN-II

This study tests the hypothesis that the control of vascular smooth mu scle cell (VSMC) apoptosis is regulated by the antagonistic balance be tween vasoactive substances such as NO and angiotensin II (Aug II). Mo reover, it is postulated that the cellular signaling pathways involved in regulating vessel tone are also coupled to the regulation of progr ammed cell death. Using an in vitro model system, we documented that t he addition of NO donor molecules S-nitroso-N-acetylpenicillamine or s odium nitroprusside to VSMC dose-dependently induced apoptosis as docu mented by DNA laddering and quantified by analysis of cellular chromat in morphology. The mediator role of the guanylate cyclase signaling pa thway in NO-induced apoptosis was evidenced by (1) induction of apopto sis by the 8-bromo-cGMP analogue, (2) potentiation of NO-induced apopt osis by cGMP-specific phosphodiesterase inhibition. and (3) the preven tion of NO-induced apoptosis by the inhibition of the cGMP-dependent p rotein kinase I alpha. In contrast, Ang II directly antagonized NO don or- and cGMP analogue-induced apoptosis via activation of the type I A ng II receptor. These findings suggest that the countervailing balance between NO and Ang II may determine the overall cell population withi n the vessel wall by regulating genetic programs determining cell deat h as well as cell growth.