LRRC8A deficiency in vascular smooth muscle cells promotes STAT1/Calcrl/Ramp1 signaling to decrease blood pressure.

Abstract

Blood pressure (BP) is positively correlated with the activity of volume-regulated chloride channels (VRCCs) in vascular smooth muscle cells (VSMCs) during hypertension, and LRRC8A has recently been identified as the key molecular component of VRCCs. However, the role of LRRC8A in BP regulation remains unclear. Here, we generated SMC-specific LRRC8A knockout (CKO) mice and performed bulk RNA-sequencing, ChIP-sequencing, and coimmunoprecipitation coupled with mass spectrometry to elucidate the underlying mechanisms. We found that systolic BP was largely reduced in CKO mice under basal conditions as well as in those with angiotensin II- or DOCA-salt-induced hypertension. Aortas from CKO mice exhibited decreased vasoconstriction, whereas vasodilation and cardiac function remained unaffected. Mechanistically, LRRC8A deletion reduced STAT1 degradation and enhanced Calcrl transcription, thereby strengthening the inhibitory effect of Calcrl on myosin light chain phosphorylation and identifying LRRC8A deficiency as a negative regulator of VSMC contractility. Moreover, LRRC8A deficiency promoted the interaction between CSRP2 and PIAS1 and subsequently suppressed STAT1 degradation. Pharmacological inhibition of STAT1 with fludarabine abolished the protective effects of LRRC8A deficiency against hypertension and vasoconstriction. In summary, our findings reveal an essential role for LRRC8A in BP regulation and highlight a potential therapeutic strategy for hypertension.