Gastroenterology

Gastroenterology

Volume 125, Issue 1, July 2003, Pages 58-69
Gastroenterology

Clinical-alimentary tract
Acquired microvascular dysfunction in inflammatory bowel disease: loss of nitric oxide-mediated vasodilation

https://doi.org/10.1016/S0016-5085(03)00699-1Get rights and content

Abstract

Background & Aims:

Inflammatory bowel disease (IBD; i.e., Crohn’s disease, ulcerative colitis) is characterized by refractory inflammatory ulceration and damage to the intestine. Mechanisms underlying impaired healing are not defined. Because microvascular dysfunction resulting in diminished vasodilatory capacity and tissue hypoperfusion is associated with impaired wound healing, we hypothesized that microvascular dysfunction may also occur in chronic IBD.

Methods:

Intact submucosal arterioles from control, involved, and uninvolved IBD specimens were assessed using in vitro videomicroscopy to assess endothelium-dependent vasodilation in response to acetylcholine (Ach) and fluorescence microscopy to detect oxyradicals.

Results:

Normal microvessels dilated in a dose-dependent and endothelium-dependent manner to Ach (maximum, 82% ± 2%; n = 34). Inhibition of nitric oxide synthase with NG-nitro-l-arginine methyl ester (l-NAME) reduced maximal dilation to 54% ± 6% (P < 0.05, n = 7), and further reduction was observed after inhibiting cyclooxygenase (indomethacin; 23% ± 10%, n = 6). Chronically inflamed IBD microvessels showed significantly reduced Ach-induced vasodilation (maximum, 15% ± 2%; n = 33), with no effect of l-NAME. Indomethacin eliminated the remaining Ach-induced vasodilation, resulting in frank vasoconstriction (−54% ± 9%, n = 6). Uninvolved IBD gut vessels and non-IBD inflammatory controls responded in a fashion similar to normal vessels. IBD-involved microvessels generated significantly higher levels of reactive oxygen species compared with control and uninvolved IBD vessels (P < 0.01).

Conclusions:

Human intestinal microvessels from chronically inflamed IBD show microvascular endothelial dysfunction, characterized by loss of NO-dependent dilation that may contribute to reduced perfusion, poor wound healing, and maintenance of chronic inflammation.

Section snippets

General preparation

All protocols were approved by the institutional review board of the Medical College of Wisconsin. Human submucosal arterioles were dissected from full-thickness intestinal specimens obtained from patients undergoing bowel operations. Immediately following resection in the operating room, excised tissues were placed in Krebs’ buffer solution (4°C) with the following composition (in mmol/L): NaCl, 118; KCl, 4.7; CaCl2, 2.5; KH2PO4, 1.2; MgSO4, 1.2; NaHCO3, 20; Na2/ethylenediaminetetraacetic

Isolation of microvessels

Submucosal microvessels were isolated from 34 controls and 33 patients with IBD (19 with CD and 14 with UC). Microvessels ranging from 56 to 302 μm in diameter were dissected from full-thickness intestinal specimens and used in all experiments (Figure 1A). Clinical data on the patients with IBD are included in Table 1. Mean passive luminal diameters of intestinal microvessels isolated from these clinical groups were similar (Table 2).

Impaired endothelium-dependent dilation in IBD

Vessels isolated from histologically normal bowel in

Discussion

This study is the first to directly examine vasodilator responses in human intestinal microvessels in healthy subjects and in patients with CD and UC. Our investigation shows a profound impairment in microvascular endothelial function in chronically inflamed IBD patient tissues that is absent in adjacent ”normal” segments or in vessels from patients with active inflammatory intestinal conditions. This is significant, because the microvasculature plays a fundamental role in health and tissue

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    Supported by the Cardiovascular Center and Impulse Dynamics, the Crohn’s and Colitis Foundation of America (to D.G.B.), and the Digestive Disease Center at the Medical College of Wisconsin.

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