Abstract 2792: Vascular Endothelial Growth Factor Deficiency: A Potential Cause of Left Ventricular Hypoplasia
Hypoplasia of the left ventricle (HLV) is a devastating consequence of perturbations in cardiac development. We evaluated genes acting downstream in cardiac development to understand the pathologic basis of LV hypoplasia. A decrease in myocardial capillarization has been reported in hypoplastic left heart syndrome (HLHS). Vascular endothelial growth factor (VEGF) is critical to endothelial proliferation and coronary development. We studied the expression of VEGF and its upstream regulators: serum response factor (SRF) - a transcriptional activator of VEGF, fibronectin - an extracellular matrix protein that enhances VEGF activity, connexin43 - an enhancer of endothelial cell coupling and p53 and PTEN - inhibitors of VEGF.
METHODS: Gene expression using real-time PCR and protein expression using Western Blot was measured in left ventricular (LV) myocardium obtained at the time of cardiac transplant from 7 patients (pts) with HLV (2003–2005). This was compared with the myocardial expression from 6 normally developed LVs using Student T test.
VEGF gene expression was 3-fold lower in HLVs compared to controls. This was associated with significantly lower VEGF protein expression (P<0.05). The expression of other growth factors was not different between hypoplastic and normal LV.
Upstream transcriptional regulator, SRF, expression was 7 fold higher in HLV (p<0.001) with a higher protein expression (p<0.01).
Connexin43 and fibronectin, which interact with other growth factors and regulate capillary growth, were 5–8 fold higher in HLV (p<0.05). (iv) VEGF inhibitors, p53 and PTEN, were 8–9 fold higher in HLV (p<0.01). Protein expression of p53 was also higher in HLV (p<0.01). Therefore despite upregulation of upstream transcriptional factors like SRF, VEGF remained downregulated possibly due to inhibition by p53 and PTEN.
CONCLUSION: This is the first report of altered VEGF signaling in a study of human hearts with LV hypoplasia. Since VEGF is important in cardiac development, future applications include therapeutic gene transfer of VEGF antenatally during the critical period of ventricular growth. This may improve the growth potential of the hypoplastic LV in children with complex congenital cardiac malformations.