Perivascular adipose and perivascular nerve dysfunction in inflammatory bowel disease is reversed after macrophage depletion
Authors: Boerman Erika , Jenkins Samuel , Ramos Kassandra , Grunz Elizabeth 
Published: May 2023

Objective: Perivascular adipose tissue (PVAT) of mesenteric arteries (MAs) houses an array of immune cells and modulates vasomotor function. Changes in PVAT immune cell content and vasomotor effects are evident in cardiovascular diseases but have not been studied in Inflammatory Bowel Disease (IBD), where altered intestinal macrophage populations and impaired blood flow are evident. Thus, we hypothesized that (1) PVAT macrophage population expands with IBD, (2) IBD alters the role of PVAT in modulating sympathetic constriction and sensory dilation and (3) macrophage depletion improves PVAT and perivascular nerve function. Methods: Male and female IL10-/- mice were gavaged with H. hepaticus at weaning and developed IBD for 90d. Age-matched C57BL/6 mice served as controls. Mice then received two injections of PBS- or clodronate (CLOD)-containing liposomes to deplete macrophages. For immunofluorescence, MA PVAT was fixed, labeled for F4/80+ macrophages and confocally imaged. Fluorescence area was quantified and compared via nested one-way ANOVA. Perivascular nerve function was assessed using pressure myography of MAs. Sympathetic nerves were stimulated using electrical field stimulation (EFS, 50V, 1-16 Hz), and sensory nerves were stimulated (50V, 8 and 16Hz) in preconstricted arteries, with responses compared via two-way ANOVA. Results: IBD caused a ~200% increase in PVAT F4/80+ area (P<0.001). CLOD decreased F4/80+ area similar to Control-PBS and Control-CLOD PVAT levels (P=0.58 and 0.26). In cannulated MAs, sympathetic constrictions were similar in Control and IBD arteries -PVAT. In Control MAs, PVAT was anti-contractile: max EFS constriction decreased ~25% in +PVAT vs -PVAT arteries (P=0.005). PVAT became pro-contractile in IBD arteries, increasing max EFS constriction ~60% (P-0.004). Sympathetic constrictions were similar after CLOD vs PBS liposomes in Control -PVAT (P=0.54), Control +PVAT (P=0.80), or IBD -PVAT (P=0.77). In contrast, CLOD reversed PVAT pro-contractility in IBD-PBS +PVAT vs IBD-CLOD +PVAT arteries (P<0.001), decreasing max constriction ~25% back to Control levels. Subsequent studies measured sensory vasodilation in Control and IBD arteries +/- PVAT treated with PBS or CLOD. In Control-PBS, max sensory dilation was increased ~20% in +PVAT vs -PVAT arteries (P=0.02). IBD-PBS exhibited >75% decrease in max sensory vasodilation compared to Control in both -PVAT and +PVAT groups (P<0.001). CLOD significantly increased max sensory vasodilation ~250% in IBD -PVAT (P<0.001) and ~200% in IBD +PVAT (P<0.001), although neither group reached the max dilation of Control +/- PVAT. Conclusions: Macrophages accumulate in MA PVAT with IBD, causing it to become pro-contractile and impair perivascular sensory vasodilation. Macrophage depletion reverses PVAT pro-contractility and restored sensory vasodilation, making PVAT macrophages a potential target to restore impaired blood flow in IBD. R01HL157038, R00HL129196 to EMB This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.