Senolytics prevent caveolar CaV3.2‐RyR axis malfunction in old vascular smooth muscle

Abstract

AbstractAging is a major risk factor for cardiovascular diseases. Our previous studies demonstrate that aging impairs the caveolar T‐type CaV3.2‐RyR axis for extracellular Ca2+ influx to trigger Ca2+ sparks in vascular smooth muscle cells (VSMCs). We hypothesize that the administration of senolytics, which can selectively clear senescent cells, could preserve the caveolar CaV3.2‐RyR axis in aging VSMCs. In this study, 10‐month‐old mice were administered the senolytics cocktail consisting of dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi‐weekly for 4 months. Using VSMCs from mouse mesenteric arteries, we found that Ca2+ sparks were diminished after caveolae disruption by methyl‐β‐cyclodextrin (10 mM) in cells from D + Q treated but not vehicle‐treated 14‐month‐old mice. D + Q treatment promoted the expression of CaV3.2 in 14‐month‐old mesenteric arteries. Structural analysis using electron tomography and immunofluorescence staining revealed the remodeling of caveolae and co‐localization of CaV3.2‐Cav‐1 in D + Q treatment aged mesenteric arteries. In keeping with theoretical observations, Cav3.2 channel inhibition by Ni2+ (50 μM) suppressed Ca2+ in VSMCs from the D + Q group, with no effect observed in vehicle‐treated arteries. Our study provides evidence that age‐related caveolar CaV3.2‐RyR axis malfunction can be alleviated by pharmaceutical intervention targeting cellular senescence. Our findings support the potential of senolytics for ameliorating age‐associated cardiovascular disease.