Lack of vitamin D receptor causes stress-induced premature senescence in vascular smooth muscle cells through enhanced local angiotensin-II signals

•Lacking vitamin D signalling induces premature senescence in vascular smooth muscle cells.•The increase in senescence is mediated by an increase in cathepsin D mediated angiotensin-II expression.•The increase in angiotensin-II induces an increase in NADPH oxidase-mediated free radical production.•All these changes induce a decrease in proliferation of vascular smooth muscle cells.

ObjectivesThe inhibition of the renal renin-angiotensin system by the active form of vitamin D contributes to the cardiovascular health benefits of a normal vitamin D status. Local production of angiotensin-II in the vascular wall is a potent mediator of oxidative stress, prompting premature senescence. Herein, our objective was to examine the impact of defective vitamin D signalling on local angiotensin-II levels and arterial health.MethodsPrimary cultures of aortic vascular smooth muscle cells (VSMC) from wild-type and vitamin D receptor-knockout (VDRKO) mice were used for the assessment of cell growth, angiotensin-II and superoxide anion production and expression levels of cathepsin D, angiotensin-II type 1 receptor and p57Kip2. The in vitro findings were confirmed histologically in aortas from wild-type and VDRKO mice.ResultsVSMC from VDRKO mice produced more angiotensin-II in culture, and elicited higher levels of cathepsin D, an enzyme with renin-like activity, and angiotensin-II type 1 receptor, than wild-type mice. Accordingly, VDRKO VSMC showed higher intracellular superoxide anion production, which could be suppressed by cathepsin D, angiotensin-II type 1 receptor or NADPH oxidase antagonists. VDRKO cells presented higher levels of p57Kip2, impaired proliferation and premature senescence, all of them blunted upon inhibition of angiotensin-II signalling. In vivo studies confirmed higher levels of cathepsin D, angiotensin-II type 1 receptor and p57Kip2 in aortas from VDRKO mice.ConclusionThe beneficial effects of active vitamin D in vascular health could be a result of the attenuation of local production of angiotensin-II and downstream free radicals, thus preventing the premature senescence of VSMC.