Brain derived neurotrophic factor is an endothelial cell survival factor required for intramyocardial vessel stabilization

Brain derived neurotrophic factor, BDNF, is a neurotrophin best characteriz ed for its survival ana differentiative effects on neurons expressing the t rk B receptor tyrosine kinase, Although many of these neurons are lost in t he BDNF-/- mouse, the early postnatal lethality of these animals suggests a wider function for this growth factor. Here, we demonstrate that deficient expression of BDNF impairs the survival of endothelial cells in intramyoca rdial arteries and capillaries in the early postnatal period, although the embryonic vasculature can remodel into arteries, capillaries and veins. BDN F deficiency results in a reduction in endothelial cell-cell contacts and i n endothelial cell apoptosis, leading to intraventricular wall hemorrhage, depressed cardiac contractility and early postnatal death. Vascular hemorrh age is restricted to cardiac vessels, reflecting the localized expression o f BDNF and trk B by capillaries and arterioles in this vascular bed. Conver sely, ectopic BDNF overexpression in midgestational mouse hearts results in an increase in capillary density. Moreover, BDNF activation of endogenous trk B receptors supports the survival of cardiac microvascular endothelial cells cultured from neonatal mice. These results establish an essential rol e for BDNF in maintaining vessel stability in the heart through direct angi ogenic actions on endothelial cells.