Gastroenterology

Gastroenterology

Volume 138, Issue 7, June 2010, Pages 2457-2467.e5
Gastroenterology

Basic—Alimentary Tract
Corticotropin-Releasing Hormone Family of Peptides Regulates Intestinal Angiogenesis

https://doi.org/10.1053/j.gastro.2010.02.055Get rights and content

Background & Aims

The corticotrophin-releasing hormone (CRH) family of peptides modulates intestinal inflammation and the CRH receptor 2 (CRHR2) suppresses postnatal angiogenesis in mice. We investigated the functions of CRHR1 and CRHR2 signaling during intestinal inflammation and angiogenesis.

Methods

The activities of CRHR1 and CRHR2 were disrupted by genetic deletion in mice or with selective antagonists. A combination of in vivo, ex vivo, and in vitro measures of angiogenesis were used to determine their activity. CRHR1−/− mice and CRHR2−/− mice with dextran sodium sulfate–induced colitis were analyzed in comparison with wild-type littermates (controls).

Results

Colitis was significantly reduced in mice in which CRHR1 activity was disrupted by genetic deletion or with an antagonist, determined by analyses of survival rate, weight loss, histological scores, and cytokine production. Inflammation was exacerbated in mice in which CRHR2 activity was inhibited by genetic deletion or with an antagonist, compared with controls. The inflamed intestines of CRHR1−/− mice had reduced microvascular density and expression of vascular endothelial growth factor (VEGF)-A, whereas the intestines of CRHR2−/− mice had increased angiogenesis and VEGF-A levels. An antagonist of VEGFR2 activity alleviated colitis in CRHR2−/− mice. Ex vivo aortic vessel outgrowth was reduced when CRHR1 was deficient but increased when CRHR2 was deficient. The CRHR1 preferred agonist CRH stimulated tube formation, proliferation, and migration of cultured intestinal microvascular endothelial cells by phosphorylating Akt, whereas the specific CRHR2 agonist Urocortin III had opposite effects.

Conclusion

CRHR1 promotes intestinal inflammation, as well as endogenous and inflammatory angiogenesis whereas CRHR2 inhibits these activities.

Section snippets

Animal Models

CRHR1 heterozygote mice (Crhr1tm1Klee) were obtained from The Jackson Laboratory. CRHR1-deficient mice and their wild-type littermates (M&F, 8–12 weeks) were derived from heterozygous breedings. CRHR2-deficient mice were a gift from Dr W. Vale (Salk Institute, La Jolla, CA) and had been backcrossed onto a B6 background (>N10). CRHR2-deficient mice and their wild-type littermates (M&F, 8–12 weeks) were derived from heterozygous breedings. To induce colitis, mice were fed with DSS (4%, MP

Genetic Deficiency of CRHR1 Ameliorates, but CRHR2 Deficiency Exacerbates Intestinal Inflammation

We first determined the differential function of CRHR1 and CRHR2 in intestinal inflammation. CRHR1−/−, CRHR2−/−, and their littermate control mice were subjected to DSS-induced colitis for 14 days and the inflammatory response was evaluated. Mortality and weight loss were reduced in CRHR1−/− mice compared with their littermate control CRHR1+/+ mice (Figure 1A and B). In contrast, mortality and weight loss were increased in CRHR2−/− mice compared with their littermate control CRHR2+/+ mice (

CRH Family of Peptides Differentially Regulates Intestinal Angiogenesis

Here we identify what we believe to be a novel function for the CRH family of peptides as a regulator of angiogenesis in the inflamed intestine. Our first indication that endogenous CRH might be proangiogenic came from studies in mice with global deletion of CRHR1 that showed severely delayed vessel outgrowth from aortic explants. CRH is densely expressed on SMCs in the vascular system15 and CRH-producing tumor cells significantly enhance angiogenesis when injected subcutaneously into nude mice,

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    Conflicts of interest The authors disclose no conflicts.

    Funding This work was supported by a Young Clinical Scientist Award from “FAMRI, Inc.” (EI and SHR) and by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney DiseasesKO1 DK083336 (EI), KO1 DK079015 (SHR), RO1 DK50894, and RO1 DK69854 (CF), VA Career Scientist Award and DK41301 (YT), and PO1 DK33506 and RO1 DK072471 (CP).

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