| The Ras activator RasGRP3 mediates diabetes-induced embryonic defects and affects endothelial cell migration. | |
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MedLine Citation:
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PMID: 21474816 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: 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. METHODS AND 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. |
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Authors:
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Paramjeet K Randhawa; Svetlana Rylova; Jessica Y Heinz; Stephanie Kiser; Joanna H Fried; William P Dunworth; Amanda L Anderson; Andrew T Barber; John C Chappell; David M Roberts; Victoria L Bautch |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-04-07 |
Journal Detail:
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Title: Circulation research Volume: 108 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-05-13 Completed Date: 2011-07-18 Revised Date: 2011-09-22 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 1199-208 Citation Subset: IM |
Affiliation:
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Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Movement / genetics* Cells, Cultured Diabetes Mellitus, Experimental / genetics, metabolism*, pathology* Embryo Culture Techniques Embryonic Development / genetics Embryonic Stem Cells / metabolism*, pathology Endothelial Cells / metabolism*, pathology Female Mice Mice, Inbred C57BL Mice, Knockout Pregnancy Pregnancy Complications, Cardiovascular / genetics, metabolism*, pathology* ras Guanine Nucleotide Exchange Factors / deficiency, genetics, physiology* |
| Grant Support | |
ID/Acronym/Agency:
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HL43174/HL/NHLBI NIH HHS; HL83262/HL/NHLBI NIH HHS; R01 HL043174-20/HL/NHLBI NIH HHS; R01 HL083262-04/HL/NHLBI NIH HHS; T32 HD046369-05/HD/NICHD NIH HHS; T32 HD46369/HD/NICHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/RasGRP3 protein, mouse; 0/ras Guanine Nucleotide Exchange Factors |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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