Vascular endothelial growth factor expression coincides with coronary vasculogenesis and angiogenesis

Vascular endothelial growth factor (VEGF) plays an important role in early embryonic vasculogenesis. To establish its temporal expression and localiza tion in the heart during development, we studied rat hearts from the first embryonic day (E) of myocardial vascular tube formation through the early p ostnatal period. Ventricular VEGF immunoreactivity was noted in the epicard ium and the thin underlying myocardium in E10 ventricles. During the earlie st stages of vascularization (E13-E16) immunoreactivity was highest in the compact myocardium nearest the epicardium, and subsequently (E18 and therea fter) became more evenly distributed transmurally, By birth (E22) immunorea ctivity was most intense around microvessels, Similarly, VEGF mRNA localiza tion, demonstrated by in situ hybridization, was initially highest near the epicardium and then became more evenly distributed transmurally by late ge station. Within the interventricular septum, the highest expression occurre d in the middle of the wall where it correlated with the greatest vasculari zation. Northern blot analysis showed that from E12 through the first 10 da ys of postnatal life, VEGF was two to three times higher than in the adult. Western blot analysis showed that VEGF tended to be higher in the atria th an the ventricles, and negligible in the outflow tract. Our data indicate t hat VEGF localization and expression 1) correspond to the pattern of vascul arization in the embryonic/fetal heart, and 2) remain high during the early postnatal period when capillary proliferation is high. Because VEGF is sti mulated by hypoxia, its preferential mRNA expression near the epicardium, t hat is, farthest from the ventricular lumen and the O-2 source, fits with t he hypothesis that a hypoxic gradient is a driving force in the transmural vascularization process. (C) 1999 Wiley-Liss,Inc.