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Impaired Perivascular Nerve Function of Mesenteric Arteries in a Murine Model of Inflammatory Bowel Disease
Author(s) -
Boerman Erika M,
Hart Marcia L,
Franklin Craig L,
Segal Steven S
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1015.5
Subject(s) - calcitonin gene related peptide , medicine , substance p , endocrinology , sodium nitroprusside , mesenteric arteries , vasodilation , inflammatory bowel disease , irritable bowel syndrome , vasoconstriction , sensory nerve , neuropeptide y receptor , stimulation , neuropeptide , sensory system , receptor , artery , disease , biology , nitric oxide , neuroscience
Mesenteric arteries (MAs) are innervated by perivascular sympathetic and sensory nerves that regulate intestinal perfusion via vasoconstriction and vasodilation, respectively. During inflammatory bowel disease (IBD), levels of circulating anti‐inflammatory sensory neuropeptide calcitonin gene‐related peptide (CGRP) and pro‐inflammatory substance P (SP) correlate with decreased and increased severity of IBD, respectively. However, neither perivascular nerve function nor reactivity to sympathetic and sensory neurotransmitters (NTs) have been assessed in MAs during IBD. We hypothesized that MA reactivity to endogenous and exogenous NTs are impaired during IBD. Male and female B6.129P2‐IL10 tm1Cgn /J (IL10 −⁄− ) mice were inoculated with Helicobacter hepaticus by gastric gavage at 2 and 4 days post‐weaning and allowed to develop IBD for 90 days. Non‐inoculated littermates, which do not develop IBD, served as controls (n = 5–8/group). Second‐order MAs were isolated, cannulated, pressurized to 100 cm H 2 O at 37°C with diameter recorded continuously during superfusion of drug solutions and/or electrical field stimulation (EFS, 50V, 2ms, 1–16Hz). Maximal diameters (D max ) with 10 −5 M sodium nitroprusside were larger in control (234 ± 5 μm) vs IBD (215 ± 5 μm) MAs (P<0.05). Additional MAs were fixed and stained for all perivascular nerves (PGP9.5) while sensory nerves were stained for SP and CGRP. Exogenous norepinephrine (NE, 10 −9 to 10 −5 M) produced similar maximum constrictions in control and IBD MAs (60 ± 5 vs 64 ± 3% μm; LogEC 50 = −6.6 ± 0.1 and −6.9 ± 0.1), while EFS produced greater constriction in control (40 ± 2%) vs IBD (33 ± 3%; P<0.05) MAs. To study vasodilation, MAs were preconstricted with NE or phenylephrine (10 −6 M). Exogenous CGRP (10 −10 to 10 −6 M) evoked similar peak dilations in control and IBD MAs (74 ± 5% and 61 ± 10% of D max ; LogEC 50 : −8.6 ± 0.2 and −8.2 ± 0.4). In contrast, despite similar LogEC 50 values (−8.4 ± 0.2 and −8.6 ± 0.5), efficacy of MA dilations to SP (10 −10 to 10 −6 M) was reduced by ~half for IBD (23 ± 5%) vs control (51 ± 5%; P<0.05). Following depletion of sensory NTs (capsaicin; 10 −5 M), EFS evoked greater constriction of control (48 ± 1%) vs IBD (35 ± 3%, P<0.05) MAs, while following depletion of sympathetic NTs (guanethidine, 10 −5 M), EFS elicited greater vasodilation in control (68 ± 13%) vs IBD (26 ± 7%; P<0.05) MAs that was blocked by pre‐treatment with capsaicin (10 −5 M). Immunostaining revealed dense perivascular nerves for PGP9.5 and CGRP with fewer SP‐containing nerves from both control and IBD mice. These findings from MAs of IBD mice reveal: 1) Impaired sympathetic neurotransmission with intact reactivity to NE; 2) Impaired sensory neurotransmission and diminished efficacy of SP with preservation of reactivity to CGRP. Our studies identify MAs as integral to the pathogenesis of IBD. Diminished perivascular nerve function with depressed efficacy of SP are markers of vascular dysfunction in this murine model. Support or Funding Information K99HL129196 to EMB & R37HL041026 to SSS