Microvascular Notch Signaling Is Upregulated in Response to Vascular Endothelial Growth Factor and Chronic Myocardial Ischemia

Abstract

Background: Notch signaling is a highly conserved pathway that promotes vascular and myocardial growth. The hypothesis that exogenous vascular endothelial growth factor (VEGF) administration to ischemic myocardium would enhance the neovascular response and upregulate Notch signaling was assessed. Methods and Results: Fourteen male Yorkshire swine underwent placement of an ameroid constrictor on the left circumflex artery to induce chronic myocardial ischemia with half of the animals receiving perivascular VEGF to the ischemic area. The remote territory served as the normal ventricle control (NV), while the 2 experimental groups consisted of the area at risk of the non-VEGF animals (AAR) and the area at risk of animals treated with VEGF (VEGF). Capillary and arteriolar density was significantly increased in the VEGF group as compared to both NV and AAR. Expression of Notch receptors and pro-neovascular Notch ligands was significantly higher in the VEGF group. Both Jagged 1 and Notch 3 were the most highly concentrated in the smooth muscle wall of arterioles. Conclusions: VEGF administration to chronically ischemic myocardium significantly augmented the neovascular response by an increase in both capillary and arteriolar density, and resulted in an upregulation of several Notch receptors and ligands, which were not upregulated with ischemia alone. These findings suggest that the augmented neovascular response seen with VEGF administration was through the VEGF-induced upregulation of Notch signaling.  (Circ J 2014; 78: 743–751)