ENDOTHELIUM-MODULATED PROLIFERATION OF MEDIAL SMOOTH-MUSCLE CELLS - INFLUENCE OF ANGIOTENSIN-II AND CONVERTING-ENZYME INHIBITION

This study investigated the role of the endothelium and angiotensin II (Ang II) in regulating medial smooth muscle cell (SMC) proliferation. [H-3]-thymidine incorporation into medial SMC of rat arteries was exa mined in vivo using ballooned rat carotid arteries, as well as in vitr o, using cultures of aortic tissue rings (organoids). In vivo, maximal medial [H-3]-thymidine incorporation occurred within 3 days post-ball ooning. In endothelium-denuded organoids, maximum medial DNA synthesis was achieved after 7 days of culture. [H-3]-thymidine-labelling of SM C in intact organoids (with endothelium) increased minimally during cu lture indicating that the endothelium provided protection with respect to medial proliferation under basal conditions (culture in the presen ce of 1% plasma-derived serum). Inclusion of 10(-7)M Ang II significan tly elevated medial [H-3]-thymidine incorporation above that in contro l cultures. The stimulatory effect of Ang II was much more pronounced in intact organoids than in endothelium-denuded organoids, indicating synergistic growth regulation by Ang II and endothelium-derived factor s. When organoids were cultured in the combined presence of Ang II and the ACE inhibitor cilazaprilat, labelling indices of intact organoids were also significantly increased above control, but to a lower level than those obtained in the presence of Ang II alone. However, for end othelium-denuded organoids, medial [H-3]-thymidine incorporation in th e combined presence of Ang II and cilazaprilat was not significantly d ifferent from that in untreated controls. Thus, cilazaprilat exerts bo th endothelium-dependent and endothelium-independent negative regulato ry effects on medial SMC proliferation.