Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri.
Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri.
Am J Physiol Heart Circ Physiol. 2021 May 1;320(5):H1887-H1902. doi: 10.1152/ajpheart.00037.2021. Epub 2021 Mar 12.
Inflammatory bowel disease (IBD) is associated with both impaired intestinal blood flow and increased risk of cardiovascular disease, but the functional role of perivascular nerves that control vasomotor function of mesenteric arteries (MAs) perfusing the intestine during IBD is unknown. 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. In MAs from an interleukin-10 knockout (IL-10) mouse model, IBD significantly impairs electrical field stimulation (EFS)-mediated sensory vasodilation and inhibition of sympathetic vasoconstriction, despite decreased sympathetic nerve density and vasoconstriction. The MA content and EFS-mediated release of both CGRP and SP are decreased with IBD, but IBD has unique 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 key finding is that blockade of SP receptors restores EFS-mediated sensory vasodilation and enhanced CGRP-mediated vasodilation in MAs from IBD but not Control mice. Together, these data suggest that an aberrant role for the perivascular sensory neurotransmitter SP and its downstream signaling in MAs underlies vascular dysfunction with IBD. We propose that with IBD, SP signaling impedes CGRP-mediated sensory vasodilation, contributing to impaired blood flow. Thus, substance P and NK1 receptors may represent an important target for treating vascular dysfunction in IBD. Our study is the first to show that IBD causes profound impairment of sensory vasodilation and inhibition of sympathetic vasoconstriction in mesenteric arteries. This occurs alongside decreased SP-containing nerve density and increased expression of NK1 receptors for SP. In contrast, CGRP dilation, nerve density, and receptor expression are unchanged. Blocking NK1 receptors restores sensory vasodilation in MAs and increases CGRP-mediated vasodilation, indicating that SP interference with CGRP signaling may underlie impaired sensory vasodilation with IBD.
炎症性肠病（IBD）与肠道血流受损和心血管疾病风险增加有关，但控制供应肠道的肠系膜动脉（MA）血管舒缩功能的血管周围神经的功能作用尚不清楚。由于血管周围感觉神经及其递质降钙素基因相关肽（CGRP）和 P 物质（SP）是血管舒张和炎症反应的重要介质，我们的目标是确定 IBD 相关的血管周围感觉神经功能和血管神经递质信号转导缺陷。在白细胞介素-10 敲除（IL-10）小鼠模型的 MA 中，尽管交感神经密度和血管收缩减少，但 IBD 显著损害电刺激（EFS）介导的感觉性血管舒张和抑制交感神经血管收缩。IBD 时 MA 内容物和 EFS 介导的 CGRP 和 SP 释放均减少，但 IBD 对每种递质有独特的影响。CGRP 神经密度、受体表达、超极化和血管舒张在 IBD 时得到保留。相比之下，SP 神经密度和受体表达增加，SP 超极化和血管舒张受损。一个关键发现是，在 IBD 而非对照小鼠的 MA 中，阻断 SP 受体可恢复 EFS 介导的感觉性血管舒张和增强的 CGRP 介导的血管舒张。这些数据表明，MA 中血管周围感觉神经递质 SP 及其下游信号的异常作用是 IBD 血管功能障碍的基础。我们提出，在 IBD 中，SP 信号阻碍 CGRP 介导的感觉性血管舒张，导致血流受损。因此，P 物质和 NK1 受体可能是治疗 IBD 血管功能障碍的重要靶点。我们的研究首次表明，IBD 导致肠系膜动脉感觉性血管舒张和抑制交感神经血管收缩的严重损害。这与 SP 含量神经密度降低和 SP 的 NK1 受体表达增加同时发生。相比之下，CGRP 扩张、神经密度和受体表达保持不变。阻断 NK1 受体可恢复 MA 中的感觉性血管舒张并增加 CGRP 介导的血管舒张，表明 SP 对 CGRP 信号的干扰可能是 IBD 感觉性血管舒张受损的基础。
