Smooth Muscle LRRC8A Knockout Preserves Vascular Function in Ang II Hypertension

Ang II (angiotensin II) causes hypertension and vascular inflammation both directly and indirectly via cytokines, including TNFα (tumor necrosis factor-α). In vascular smooth muscle cells (VSMCs), Ang II and TNFα activate Nox1 (NADPH oxidase 1) to produce superoxide. TNFα receptors associate with Nox1 and LRRC8A (leucine-rich repeat containing 8A) anion channels to modulate inflammation and contractility in a RhoA-dependent manner. VSMC-specific LRRC8A knockout mesenteric arteries are protected from TNFα-induced injury, and vasodilation is preserved. We hypothesized that LRRC8A knockout would preserve vascular function and decrease blood pressure (BP) in Ang II-infused mice.

Wild-type and knockout mice received Ang II infusions for 14 days. BP was measured by radiotelemetry, and aortic and mesenteric artery function was measured by wire myography. VSMCs were isolated from male wild-type and knockout mice.

Systolic BP was not different, but knockout mice had more BP dipping during inactive periods at baseline, and dipping was preserved after Ang II. The function of knockout aortic and mesenteric vessels was less impaired by Ang II, as reflected by less augmented contraction to norepinephrine and serotonin and preserved relaxation to acetylcholine and sodium nitroprusside. Western blotting revealed increased soluble guanylate cyclase alpha and reduced CPI-17 in hypertensive knockout aortae. Consistent with lower Rho kinase activity, phosphorylation of ERM (ezrin/radixin/moesin) and cofilin was reduced in knockout VSMCs. Ang II caused less proliferation (lower PCNA [proliferating cell nuclear antigen]) and less induction of senescence in knockout vessels.

LRRC8A anion channels support VSMC inflammation and the associated vascular dysfunction, which impairs BP dipping in hypertension.