Retinoic acids inhibit angiotensin II-dependent effects in vascular smooth muscle cells: role of AP-1

Angiotensin II-driven stimulation of vascular smooth muscle cell (VSMC) growth determines the response of the vascular wall to hypertension. We, therefore, examined the effects of retinoids, powerful anti-proliferative and anti-inflammatory agents on the actions of angiotensin II and their mechanism of interaction in VSMC primary culture. VSMCs express both RXRα and RARα protein. All-trans RA inhibited angiotensin II-induced i) cell proliferation during longterm exposure dose-dependently and ii) DNA- and protein synthesis as indicated by prolin- and thymidine incorporation. RA reversed Ang II-dependent morphological changes back to a, neural-like” phenotype and completely blocked Ang II stimulation of TGFβ1 mRNA. RA inhibition of VSMC growth was mediated both via RAR- and RXR-dependent pathways as shown by synthetic receptor-specific retinoids. Transfection experiments revealed that RA inhibits Ang II actions via AP-1 but not via SRE or Cre. RARα cotransfection alters the anti-AP-1 effect of RA in a dose-dependent manner. AP-1 mediated inhibition was equipotent after cotransfection with either RARα or RXRα-constructs. Our findings demonstrate that retinoids are potent inhibitors of the proliferative actions of angiotensin II in vascular smooth muscle cells. This suggest that retinoids influence vascular changes in response to hypertension also in vivo.