Mechanism of Aging‐associated Hypertension: Role of Smooth Muscle Cell Mineralocorticoid Receptor Regulation of Vascular L‐type Calcium Channels

Abstract

Hypertension (HTN), the most prevalent cardiovascular disease risk factor, increases with age. We found that mice with SMC-specific deletion of the mineralocorticoid receptor (MR KO) lack the aging-associated rise in blood pressure (BP). We hypothesize that SMC MR contributes to BP regulation with aging by regulating vascular L-type calcium channels (LTCC). Patch clamp studies on mesenteric resistance vessel (MRV) SMC from young (3-4 mo.) and aged (9-12 mo.) MR intact and MR KO reveal reduced LTCC current density in aged MR KO (p<0.05 vs. MR intact). Fura-2 photometry studies reveal decreased MRV Ca flux in aged MR KO (p<0.05 vs. MR intact) in response to BayK (LTCC agonist). Contraction to BayK is blunted in aged MR KO MRV (p<0.05 vs. MR intact). RNA expression of Cav1.2, the pore-forming subunit of LTCC, is reduced by 60% in aged MR KO vs. MR intact MRV (p<0.05). Micro-RNA expression profiling identified miR-155 as being modulated by SMC MR with aging. MRV miR-155 expression is increased in aged MR KO (p<0.05 vs. MR intact). Ingenuity pathway analysis identified Cav1.2 as a potential target of miR-155. Overexpression of miR-155 in mouse MRV SMC reduced Cav1.2 expression by 45% (p<0.05 vs. ctrl). These data suggest that SMC MR contributes to HTN through regulating Cav1.2 expression/function, potentially via miR-155. These results enhance our basic understanding of BP control with aging, and provide support for innovative therapeutic targets to treat aging-associated HTN. Supported by HL095590-05.