Nutrient-induced hyperosmosis evokes vasorelaxation via TRPV1 channel-mediated, endothelium-dependent, hyperpolarisation in healthy and colitis mice

Abstract

Background and purpose: In humans, blood flow in the mesenteric circulation is greatly increased after meals, but the mechanisms underlying postprandial mesenteric vasorelaxation induced by nutrients and whether this process is involved in the pathogenesis of colitis, are not well understood. Here we have studied the direct actions of nutrients on mesenteric arterial tone and the underlying molecular mechanisms in healthy and colitis mice.

Experimental approach: Colitis in C57BL/6 mice was induced with dextran sodium sulphate. Nutrient-induced vasorelaxation of mesenteric arterioles from humans and mice was studied with wire myograph assays. Ca²⁺ and Na⁺ imaging were performed in human vascular endothelial cells and vascular smooth muscle cells, using selective pharmacological agents and shRNA knockdown of TRPV1 channels.

Key results: Glucose, sodium and mannitol concentration-dependently induced endothelium-dependent relaxation of human and mouse mesenteric arterioles via hyperosmotic action,. Hyperosmosis-induced vasorelaxation was almost abolished by selective blockers for TRPV1, IK_Ca and SK_Ca channels. Glucose markedly stimulated Ca²⁺ influx through endothelial TRPV1 channels, an effect attenuated by selective blockers and shRNA knockdown of TRPV1 channels. Capsaicin synergised the glucose-induced vasorelaxation. Nutrient-induced hyperosmosis also activated Na⁺ /K⁺ -ATPase and the Na/Ca exchanger (NCX) to decrease [Ca²⁺ ]_i in VSMCs. Glucose-induced vasorelaxation was impaired in mouse colitis.

Conclusion and implications: Nutrient-induced hyperosmosis evoked endothelium-dependent mesenteric vasorelaxation via the TRPV1/Ca²⁺ / endothelium-dependent hyperpolarisation pathway to increase normal mucosal perfusion, which is impaired in our model of colitis. The TRPV1/Ca²⁺ / endothelium-dependent hyperpolarisation pathway could provide novel drug targets for gastrointestinal diseases with hypoperfusion, such as chronic colitis and mesenteric ischaemia.

Keywords: TRPV1 channels; colitis; endothelium-derived hyperpolarisation; intermediate- and small-conductance Ca2+-activated K+ channels.