title: The Ras activator RasGRP3 mediates diabetes-induced embryonic defects and affects endothelial cell migration.
abstract: BACKGROUND
  Fetuses that develop in diabetic mothers have a higher incidence of birth defects that include cardiovascular defects, but the signaling pathways that mediate these developmental effects are poorly understood. It is reasonable to hypothesize that diabetic maternal effects are mediated by 1 or more pathways activated downstream of aberrant glucose metabolism, because poorly controlled maternal glucose levels correlate with the frequency and severity of the defects.
  
  
  OBJECTIVE
  We investigated whether RasGRP3 (Ras guanyl-releasing protein 3), a Ras activator expressed in developing blood vessels, mediates diabetes-induced vascular developmental defects. RasGRP3 is activated by diacylglycerol, and diacylglycerol is overproduced by aberrant glucose metabolism in diabetic individuals. We also investigated the effects of overactivation and loss of function for RasGRP3 in primary endothelial cells and developing vessels.
  
  
  RESULTS
  Analysis of mouse embryos from diabetic mothers showed that diabetes-induced developmental defects were dramatically attenuated in embryos that lacked Rasgrp3 function. Endothelial cells that expressed activated RasGRP3 had elevated Ras-ERK signaling and perturbed migration, whereas endothelial cells that lacked Rasgrp3 function had attenuated Ras-ERK signaling and did not migrate in response to endothelin-1. Developing blood vessels exhibited endothelin-stimulated vessel dysmorphogenesis that required Rasgrp3 function.
  
  
  CONCLUSIONS
  These findings provide the first evidence that RasGRP3 contributes to developmental defects found in embryos that develop in a diabetic environment. The results also elucidate RasGRP3-mediated signaling in endothelial cells and identify endothelin-1 as an upstream input and Ras/MEK/ERK as a downstream effector pathway. RasGRP3 may be a novel therapeutic target for the fetal complications of diabetes.
authors.affiliation: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Paramjeet K
authors.initials: PK
authors.lastname: Randhawa
authors.forename: Svetlana
authors.initials: S
authors.lastname: Rylova
authors.forename: Jessica Y
authors.initials: JY
authors.lastname: Heinz
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kiser
authors.forename: Joanna H
authors.initials: JH
authors.lastname: Fried
authors.forename: William P
authors.initials: WP
authors.lastname: Dunworth
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Anderson
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Barber
authors.forename: John C
authors.initials: JC
authors.lastname: Chappell
authors.forename: David M
authors.initials: DM
authors.lastname: Roberts
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bautch
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D046149:Embryo Culture Techniques; D047108:Embryonic Development / Q000235:genetics; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020663:ras Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C526545:RasGRP3 protein, mouse; D020663:ras Guanine Nucleotide Exchange Factors