Inflammatory bowel disease (IBD) decreases quality of life of those affected, and the incidence of IBD is increasing worldwide. Further, IBD is comorbid with heart disease and stroke, the two leading causes of death. IBD is associated with decreased blood flow to the intestines, with an integral yet poorly-studied role for the mesenteric resistance (MAs) arteries that control blood flow into the intestinal microcirculation. Perivascular sensory nerves (PSNs) play a critical role in regulation of vasomotor function through release of calcitonin gene-related peptide (CGRP) and substance P (SP). These polypeptides binds to their respective receptors on smooth muscle cells (SMCs) and endothelial cells (ECs) to initiate inter- and intracellular signaling that is critical to maintaining arterial blood flow and tissue perfusion. PVSNs are particularly important in effecting MA dilation. While CGRP is anti-inflammatory and may protect against IBD, SP is proinflammatory and may exacerbate the disease. Remarkably, little is known of how PVSNs are affected by and/or contribute to IBD. Therefore, the goal of this project is to define IBD-related structural and functional changes in PVSNs in light of their actions on MAs. A key emphasis is to define the actions of CGRP and SP on SMCs and ECs of MAs and thereby determine how the media and intima of resistance arteries are affected in IBD. I will test the central hypothesis that altered sensory neurotransmitter function, release and downstream signaling in SMCs and ECs of MAs lead to impaired blood flow to the intestine during IBD. [To investigate these relationships, I will use a spontaneous mouse model of chronic IBD (SAMP1/YitFc) and apply pharmacological, immunological and molecular approaches to study MAs of the terminal ileum, with key experiments repeated in the interleukin 10 (IL-10) knockout mouse model of IBD.] To determine how PSN-mediated signaling is affected within the arterial wall during IBD, intact MAs will be surgically isolated for in vitro studies and MA arcades will be studied during blood flow control in vivo.
Aim 1 will define how the density of PSNs is affected by IBD in light of the expression, distribution and functional balance of CGRP and SP and their respective receptors on SMCs and ECs.
Aim 2 will determine how PSNs control vasomotor function (i.e., changes in vessel diameter) through the release of CGRP and SP, their actions on SMCs and ECs and how these roles are affected by IBD, particularly in light of endothelial dysfunction.
Aim 3 will determine the nature of calcium signaling in ECs and SMCs that are evoked by CGRP and SP in light of vasodilation, nitric oxide production and leukocyte adhesion during IBD. This project will uniquely define the role of PSNs and their associated signaling pathways in mediating vasomotor function and therefore blood flow control, and it will determine how these pathways are affected during the pathogenesis of IBD. Results will provide new insight towards developing novel and selective therapeutic strategies for treating vascular dysfunction and impaired intestinal blood flow to improve quality of life for IBD patients.
Perivascular sensory nerves surrounding mesenteric arteries play a key role in opposing sympathetic vasoconstriction and producing vasodilation to regulate blood flow to the intestines. Blood flow and arterial vasodilation are impaired in inflammatory bowel disease through mechanisms that are poorly understood, and the neurotransmitters released from sensory nerves, calcitonin gene-related peptide and substance P are implicated in the pathogenesis of the disease. This research investigates the nature of impaired perivascular sensory nerve function in inflammatory bowel disease to understand how to improve vascular function, blood flow and quality of life in inflammatory bowel disease patients.
|Tykocki, Nathan R; Boerman, Erika M; Jackson, William F (2017) Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles. Compr Physiol 7:485-581|