Journal
JOURNAL OF CELL BIOLOGY
Volume 160, Issue 4, Pages 605-615Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200209014
Keywords
VEGF-A(165); PECAM-1; MMP-2; endocardial cushion; epithelial-mesenchymal transformation; glucose/diabetic embryopathy
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Funding
- NHLBI NIH HHS [R01-HL51018, R01 HL051018, R37-HL28373, R37 HL028373] Funding Source: Medline
- NIDDK NIH HHS [5P30-DK-45735, P30 DK045735] Funding Source: Medline
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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-A(165), 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.
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