Heparin-binding EGF-like growth factor is a potent dilator of terminal mesenteric arterioles.
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.
Zhou
Yu
Y
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.
Brigstock
David
D
Besner
Gail E
GE
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
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