Corticotropin Releasing Hormone and Urocortin 3 Stimulate Vascular Endothelial Growth Factor Expression through the cAMP/CREB Pathway.
Colonic epithelium is the first line of defense against various pathological offenses in the gut. Previous studies have shown that the peptides of the corticotropin-releasing hormone (CRH) family modulate vascular endothelial growth factor (VEGF)-A production in other cells. Here we sought to investigate whether CRH and urocortin (Ucn) 3 regulate VEGF-A secretion in colonocytes through CRH receptors and to elucidate the underlying mechanism of action. CRH and Ucn 3 significantly increased the expression levels of VEGF-A mRNA and protein through CRH receptor 1 and 2, respectively, in human colonic epithelial cells and primary mouse intestinal epithelial cells. Underlying mechanisms involve activation of adenylyl cyclase with subsequent increase of intracellular cAMP level and increased DNA binding activity of transcription factor CREB on VEGF-A promoter region. Finally, genetic deficiency of CREB decreased intestinal inflammation and VEGF-A expression in a dextran sodium sulfate-induced colitis model. These results show that activation of CRH receptors by CRH ligands stimulates VEGF-A expression in intestinal epithelial cells through the cAMP/CREB pathway. Since VEGF-A boosts inflammatory responses through angiogenesis, these data suggest that CREB may be a key effector of CRH and Ucn 3-dependent inflammatory angiogenesis.
From the Section of Inflammatory Bowel Disease & Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California 90095 and.
Sang Hoon
SH
Rhee
From the Section of Inflammatory Bowel Disease & Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California 90095 and.
Elise L
EL
Ma
College of Pharmacy, Pusan National University, Busan, 609-735, South Korea.
Yunna
Y
Lee
From the Section of Inflammatory Bowel Disease & Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California 90095 and.
Yvette
Y
Taché
From the Section of Inflammatory Bowel Disease & Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California 90095 and.
Charalabos
C
Pothoulakis
College of Pharmacy, Pusan National University, Busan, 609-735, South Korea eoim@pusan.ac.kr.
Eunok
E
Im
D000818:Animals; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D054832:Urocortins / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D054832:Urocortins; D042461:Vascular Endothelial Growth Factor A; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP
angiogenesis; cAMP response element-binding protein (CREB); colitis; corticotropin-releasing hormone; inflammatory bowel disease (IBD); urocortin; vascular endothelial growth factor (VEGF)