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bioRxiv · 10.1101/2020.04.29.066126

Altered substance P signaling underlies perivascular sensory nerve dysfunction in inflammatory bowel disease

Norton, C. E.·Grunz-Borgmann, E. A.·Hart, M.·Jones, B. W.·Franklin, C. M.·Boerman, E. M.
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Abstract

ObjectiveInflammatory Bowel Disease (IBD) is associated with cardiovascular disease risk and impaired intestinal blood flow, but the functional role of perivascular nerves that control vasomotor function of mesenteric arteries (MAs) perfusing the intestine is unknown in IBD. Because perivascular sensory nerves and their transmitters calcitonin gene-related peptide (CGRP) and substance P (SP) are important mediators of both vasodilation and inflammatory responses, our objective was to identify IBD-related deficits in perivascular sensory nerve function and vascular neurotransmitter signaling. Approach and ResultsIn MAs from an IL-10-/- mouse model, we found that IBD significantly impairs EFS-mediated sensory vasodilation and sensory inhibition of sympathetic vasoconstriction, despite decreased sympathetic nerve density and vasoconstriction. The MA content and EFS-mediated release of both CGRP and SP are slightly decreased with IBD, but IBD has different effects on each transmitter. CGRP nerve density, receptor expression, hyperpolarization and vasodilation are preserved with IBD. In contrast, SP nerve density and receptor expression are increased, and SP hyperpolarization and vasodilation are impaired with IBD. A critical finding is that blocking neurokinin 1 (SP) receptors restored EFS-mediated sensory vasodilation and enhanced CGRP-mediated vasodilation in MAs from IBD but not Control mice. ConclusionsAn aberrant role for the perivascular sensory neurotransmitter SP and its downstream signaling in MAs underlies vascular dysfunction with IBD. With IBD, SP signaling impedes CGRP-mediated sensory vasodilation, contributing to impaired blood flow. Substance P and NK1 receptors may represent an important target for treating vascular dysfunction in IBD.

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Norton, C. E., Grunz-Borgmann, E. A., Hart, M., Jones, B. W., Franklin, C. M., Boerman, E. M.. 2020-05-02. Altered substance P signaling underlies perivascular sensory nerve dysfunction in inflammatory bowel disease. https://doi.org/10.1101/2020.04.29.066126

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