Paracrine and Autocrine Functions of Brain-derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) in Brain-derived Endothelial Cells

Abstract

Brain-derived neurotrophic factor (BDNF) is expressed by endothelial cells. We investigated the characteristics of BDNF expression by brain-derived endothelial cells and tested the hypothesis that BDNF serves paracrine and autocrine functions affecting the vasculature of the central nervous system. In addition to expressing TrkB and p75 NTR and BDNF under normoxic conditions, these cells increased their expression of BDNF under hypoxia. While the expression of TrkB is unaffected by hypoxia, TrkB exhibits a base-line phosphorylation under normoxic conditions and an increased phosphorylation when BDNF is added. TrkB phosphorylation is decreased when endogenous BDNF is sequestered by soluble TrkB. Exogenous BDNF elicits robust angiogenesis and survival in three-dimensional cultures of these endothelial cells, while sequestration of endogenous BDNF caused significant apoptosis. The effects of BDNF engagement of TrkB appears to be mediated via the phosphatidylinositol (PI) 3-kinase-Akt pathway. Modulation of BDNF levels directly correlate with Akt phosphorylation and inhibitors of PI 3-kinase abrogate the BDNF responses. BDNF-mediated effects on endothelial cell survival/apoptosis correlated directly with activation of caspase 3. These endothelial cells also express p75 NTR and respond to its preferred ligand, pro-nerve growth factor (pro-NGF), by undergoing apoptosis. These data support a role for neurotrophins signaling in the dynamic maintenance/differentiation of central nervous system endothelia.Angiogenesis is a tightly controlled process in which new vessels form from those pre-existing. This process occurs in a regulated fashion during development and growth as well as in response to physiological and pathological stimuli. Angiogenesis as been shown to be a receptor-and ligand-regulated process, with a still growing, diverse number of soluble factors and their cognate receptors being involved in the different phases of the angiogenic process (1). In the developing brain, angiogenesis has been shown to be regulated by factors secreted by neuronal and glial cell populations in an orderly, spatiotemporal fashion (2). In recent studies we and others have (3,4) shown that selected angiogenic factors, VEGF 1 in particular, are capable of not only affecting a variety of endothelial behaviors but also are capable of affecting neuronal behavior in a receptor-specific fashion. Interestingly, recent studies have demonstrated that neurotrophins expressed by endothelia and are capable of influencing several endothelial cell functions including endothelial cell survival and vessel stabilization (5-7)

Selective Deletion ofBdnfin the Ventromedial and Dorsomedial Hypothalamus of Adult Mice Results in Hyperphagic Behavior and Obesity

“…There are also examples of this neurotrophin acting in an autocrine manner in the literature (Barnabe-Heider and Miller, 2003;Kim et al, 2004). In the hypothalamus, extensive expression of TrkB in the Arc, VMH, PVN, DMH, and LH suggests many potential target sites for BDNF action influencing food intake behavior Kernie et al, 2000).…”

Hippocampal Granule Neuron Number and Dentate Gyrus Volume in Antidepressant-Treated and Untreated Major Depression

“…This is consistent with the hypothesis that angiogenesis and cell survival or maturation, are regulated by the same factors. Angiogenesis and neurogenesis occur in parallel in the neurogenic niche (Palmer et al, 2000), and both are regulated by vascular endothelial growth factor (VEGF; Jin et al, 2002), BDNF, and nerve growth factor (Kim et al, 2004). Intracerebroventricular administration of VEGF in rat increases bromodeoxyuridine (BrdU) labeling of SGZ cells and immature neurons express VEGFR2/Flk-1 receptors (Jin et al, 2002).…”

ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation

“…These studies, however, do not distinguish whether mature NGF or proNGF is induced after cardiac ischemia. P75 NTR expression is also induced in the vasculature after acute injury to the aorta (Donovan et al, 1995), and p75 NTR activation promotes vascular smooth muscle and endothelial cell death in vitro (Wang et al, 2000;Kim et al, 2004). Genetic deletion of p75 NTR in mice (p75 / ) results in reduced apoptosis of vascular smooth muscle cells after vascular injury, suggesting that locally produced neurotrophins regulate this response (Kraemer, 2002).…”