Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons.
The neurovascular unit is an emerging concept that emphasizes homeostatic interactions between endothelium and cerebral parenchyma. Here, we show that cerebral endothelium are not just inert tubes for delivering blood, but they also secrete trophic factors that can be directly neuroprotective. Conditioned media from cerebral endothelial cells broadly protects neurons against oxygen-glucose deprivation, oxidative damage, endoplasmic reticulum stress, hypoxia, and amyloid neurotoxicity. This phenomenon is largely mediated by endothelial-produced brain-derived neurotrophic factor (BDNF) because filtering endothelial-conditioned media with TrkB-Fc eliminates the neuroprotective effect. Endothelial production of BDNF is sustained by beta-1 integrin and integrin-linked kinase (ILK) signaling. Noncytotoxic levels of oxidative stress disrupts ILK signaling and reduces endothelial levels of neuroprotective BDNF. These data suggest that cerebral endothelium provides a critical source of homeostatic support for neurons. Targeting these signals of matrix and trophic coupling between endothelium and neurons may provide new therapeutic opportunities for stroke and other CNS disorders.
Guo
Shuzhen
S
Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
Kim
Woo Jean
WJ
Lok
Josephine
J
Lee
Sun-Ryung
SR
Besancon
Elaine
E
Luo
Bing-Hao
BH
Stins
Monique F
MF
Wang
Xiaoying
X
Dedhar
Shoukat
S
Lo
Eng H
EH
D000818:Animals; D001921:Brain / Q000166:cytology* / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002450:Cell Communication; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000099200:Scaffold Protein ILK
D019208:Brain-Derived Neurotrophic Factor; D019012:Integrin beta1; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK