Corticotropin-releasing hormone family of peptides regulates intestinal angiogenesis.
OBJECTIVE
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.


CONCLUSIONS
CRHR1 promotes intestinal inflammation, as well as endogenous and inflammatory angiogenesis whereas CRHR2 inhibits these activities.
Im
Eunok
E
Section of Inflammatory Bowel Disease and Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA. eim@mednet.ucla.edu
Rhee
Sang Hoon
SH
Park
Yong Seek
YS
Fiocchi
Claudio
C
Taché
Yvette
Y
Pothoulakis
Charalabos
C
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000209:etiology*; D016264:Dextran Sulfate / Q000633:toxicity; D005260:Female; D007422:Intestines / Q000098:blood supply*; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000517:prevention & control; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D000099052:CRF Receptor, Type 1
D020533:Angiogenesis Inhibitors; C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D016264:Dextran Sulfate; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt