Senolytics prevent caveolar <scp>Ca_V3</scp>.<scp>2‐RyR</scp> axis malfunction in old vascular smooth muscle

Abstract Aging is a major risk factor for cardiovascular diseases. Our previous studies demonstrate that aging impairs the caveolar T‐type Ca V 3.2‐RyR axis for extracellular Ca 2+ influx to trigger Ca 2+ sparks in vascular smooth muscle cells (VSMCs). We hypothesize that the administration of senolytics(definition), which can selectively clear senescent cells, could preserve the caveolar Ca V 3.2‐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 Ca 2+ 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 Ca V 3.2 in 14‐month‐old mesenteric arteries. Structural analysis using electron tomography and immunofluorescence staining revealed the remodeling of caveolae and co‐localization of Ca V 3.2‐Cav‐1 in D + Q treatment aged mesenteric arteries. In keeping with theoretical observations, Ca v 3.2 channel inhibition by Ni 2+ (50 μM) suppressed Ca 2+ in VSMCs from the D + Q group, with no effect observed in vehicle‐treated arteries. Our study provides evidence that age‐related caveolar Ca V 3.2‐RyR axis malfunction can be alleviated by pharmaceutical intervention targeting cellular senescence(definition). Our findings support the potential of senolytics for ameliorating age‐associated cardiovascular disease.