title: Heparin-binding EGF-like growth factor is a potent dilator of terminal mesenteric arterioles.
abstract: OBJECTIVE
  We have previously shown that heparin-binding EGF-like growth factor (HB-EGF) protects the intestines from multiple forms of injury via direct cytoprotective effects on the intestinal mucosa. In this study, we examined the effects of HB-EGF on the hemodynamics of intestinal arterioles, the major resistance vessels that regulate blood flow to the intestines, as an additional mechanism of HB-EGF-mediated intestinal protection.
  
  
  METHODS
  The hemodynamic effects of HB-EGF in rodent terminal mesenteric arterioles and human submucosal arterioles were examined ex vivo using a video dimension analyzer. Cultured human intestinal microvascular endothelial cells (HIMEC) were used to elucidate the mechanisms of HB-EGF-induced vasodilation.
  
  
  RESULTS
  HB-EGF significantly increased vessel diameter under conditions of increasing intraluminal pressure and increased flow rate. These HB-EGF-mediated vasodilatory effects were observed in terminal mesenteric arterioles from adult rats and 3 day old rat pups. These effects were confirmed in submucosal arterioles from human intestine. Furthermore, HB-EGF significantly reduced endothelin-1-induced mesenteric arteriolar vasoconstriction. The vasodilatory effects of HB-EGF were blocked by ET(B) receptor antagonism in adult rat arterioles, and also by nitric oxide synthase inhibition in rat pup and human infant arterioles. In HIMEC, HB-EGF significantly increased endothelin B (ET(B)) receptor protein expression and provoked intracellular calcium mobilization.
  
  
  CONCLUSIONS
  HB-EGF is a potent vasodilator of the intestinal microvasculature, further supporting its use in diseases manifested by decreased intestinal blood flow, including necrotizing enterocolitis.
authors.affiliation: Department of Pediatric Surgery, The Ohio State University College of Medicine, Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: David
authors.initials: D
authors.lastname: Brigstock
authors.forename: Gail E
authors.initials: GE
authors.lastname: Besner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001160:Arterioles / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000098:blood supply / Q000378:metabolism; D007422:Intestines / Q000098:blood supply; D008297:Male; D008643:Mesentery / Q000098:blood supply* / Q000378:metabolism; D055806:Microvessels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000378:metabolism; D014661:Vasoconstriction; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D044023:Receptor, Endothelin B; D014665:Vasodilator Agents; D002118:Calcium