JCB logo
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published 18 February 2003. doi:10.1083/jcb.200209014
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 2193K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JCB
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Enciso, J. M.
Right arrow Articles by Madri, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Enciso, J. M.
Right arrow Articles by Madri, J. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

© The Rockefeller University Press, 0021-9525/2003/2/605 $5.00
The Journal of Cell Biology, Volume 160, Number 4, 605-615

Article

Elevated glucose inhibits VEGF-A–mediated endocardial cushion formation

: modulation by PECAM-1 and MMP-2



Josephine M. Enciso1,2, Dita Gratzinger1, Todd D. Camenisch3,4, Sandra Canosa1, Emese Pinter1,2 and Joseph A. Madri1

1 Department of Pathology, Yale University School of Medicine, New Haven, CT 06520
2 Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520
3 College of Pharmacy, University of Arizona, Tucson, AZ 85721
4 Steele Memorial Children's Research Center, College of Medicine, University of Arizona, Tucson, AZ 85724

Address correspondence to Joseph A. Madri, Dept. of Pathology, Yale University School of Medicine, 310 Cedar Street, PO Box 208023, New Haven, CT 06520-8023. Tel.: (203) 785-2763. Fax: (203) 785-7303; or Dept. Fax: (203) 785-7213. E-mail: joseph.madri{at}yale.edu

Atrioventricular (AV) septal defects resulting from aberrant endocardial cushion (EC) formation are observed at increased rates in infants of diabetic mothers. EC formation occurs via an epithelial-mesenchymal transformation (EMT), involving transformation of endocardial cells into mesenchymal cells, migration, and invasion into extracellular matrix. Here, we report that elevated glucose inhibits EMT by reducing myocardial vascular endothelial growth factor A (VEGF-A). This effect is reversed with exogenous recombinant mouse VEGF-A165, whereas addition of soluble VEGF receptor-1 blocks EMT. We show that disruption of EMT is associated with persistence of platelet endothelial cell adhesion molecule-1 (PECAM-1) and decreased matrix metalloproteinase-2 (MMP-2) expression. These findings correlate with retention of a nontransformed endocardial sheet and lack of invasion. The MMP inhibitor GM6001 blocks invasion, whereas explants from PECAM-1 deficient mice exhibit MMP-2 induction and normal EMT in high glucose. PECAM-1–negative endothelial cells are highly motile and express more MMP-2 than do PECAM-1–positive endothelial cells. During EMT, loss of PECAM-1 similarly promotes single cell motility and MMP-2 expression. Our findings suggest that high glucose-induced inhibition of AV cushion morphogenesis results from decreased myocardial VEGF-A expression and is, in part, mediated by persistent endocardial cell PECAM-1 expression and failure to up-regulate MMP-2 expression.

Key Words: VEGF-A165; PECAM-1; MMP-2; endocardial cushion; epithelial-mesenchymal transformation; glucose/diabetic embryopathy


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents