Key result
Smooth muscle LRRC8A deficiency substantially reduces systolic blood pressure and decreases vasoconstriction in mice.
Why the study?
The role of LRRC8A in vascular smooth muscle cells in blood pressure regulation remains unclear.
LRRC8A deficiency in vascular smooth muscle cells reduces blood pressure and vasoconstriction by modulating STAT1 degradation, suggesting a novel therapeutic pathway for hypertension.
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.
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Lu et al. (2026) studied Hypertension. LRRC8A deficiency (SMC-specific knockout) vs. Wild-type mice (implicit) was evaluated on Systolic blood pressure and vasoconstriction. SMC-specific LRRC8A deficiency in mice largely reduced systolic blood pressure and decreased vasoconstriction under basal conditions and in induced hypertension models.
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