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Published 18 February 2003. doi:10.1083/jcb.200209014
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© 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


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