Paracrine and autocrine functions of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brain-derived endothelial cells.
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 p75NTR 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 p75NTR 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.
Kim
Hyun
H
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520-8023, USA. drhkim@kosin.ac.kr
Li
Qi
Q
Hempstead
Barbara L
BL
Madri
Joseph A
JA
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001921:Brain / Q000166:cytology*; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D002540:Cerebral Cortex / Q000098:blood supply / Q000737:chemistry; D042783:Endothelial Cells / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000378:metabolism; D007150:Immunohistochemistry; D007163:Immunosorbent Techniques; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D020813:Receptor, trkB / Q000235:genetics / Q000502:physiology; D017475:Receptors, Nerve Growth Factor / Q000032:analysis / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D020932:Nerve Growth Factor; D020813:Receptor, trkB; D040301:Vascular Endothelial Growth Factor Receptor-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases