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The Journal of Neuroscience, March 2, 2005, 25(9):2366-2375; doi:10.1523/JNEUROSCI.5071-04.2005

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Neurobiology of Disease
Endothelial Nitric Oxide Synthase Regulates Brain-Derived Neurotrophic Factor Expression and Neurogenesis after Stroke in Mice

Jieli Chen,¹ Alex Zacharek,¹ Chunling Zhang,¹ Hao Jiang,¹ Yi Li,¹ Cynthia Roberts,¹ Mei Lu,² Alissa Kapke,² and Michael Chopp^1,3

Departments of ¹Neurology and ²Biostatistics and Research Epidemiology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, and ³Department of Physics, Oakland University, Rochester, Michigan 48309

Here, we investigate the effects of endothelial nitric oxide synthase (eNOS) on angiogenesis, neurogenesis, neurotrophic factor expression, and neurological functional outcome after stroke. Wild-type and eNOS knock-out (eNOS^-/-) mice were subjected to permanent occlusion of the right middle cerebral artery. eNOS^-/- mice exhibited more severe neurological functional deficit after stroke than wild-type mice. Decreased subventricular zone (SVZ) progenitor cell proliferation and migration, measured using bromodeoxyuridine, Ki-67, nestin, and doublecortin immunostaining in the ischemic brain, and decreased angiogenesis, as demonstrated by reduced endothelial cell proliferation, vessel perimeter, and vascular density in the ischemic border, were evident in eNOS^-/- mice compared with wild-type mice. eNOS-deficient mice also exhibited a reduced response to vascular endothelial growth factor (VEGF)-induced angiogenesis in a corneal assay. ELISAs showed that eNOS^-/- mice have decreased brain-derived neurotrophic factor (BDNF) expression but not VEGF and basic fibroblast growth factor in the ischemic brain compared with wild-type mice. In addition, cultured SVZ neurosphere formation, proliferation, telomerase activity, and neurite outgrowth but not cell viability from eNOS^-/- mice were significantly reduced compared with wild-type mice. BDNF treatment of SVZ cells derived from eNOS^-/- mice restored the decreased neurosphere formation, proliferation, neurite outgrowth, and telomerase activity in cultured eNOS^-/- SVZ neurospheres. SVZ explant cell migration also was significantly decreased in eNOS^-/- mice compared with wild-type mice. These data indicate that eNOS is not only a downstream mediator for VEGF and angiogenesis but also regulates BDNF expression in the ischemic brain and influences progenitor cell proliferation, neuronal migration, and neurite outgrowth and affects functional recovery after stroke.

Key words: eNOS; angiogenesis; neurogenesis; BDNF; neural progenitor cells; focal cerebral ischemia

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Received Dec 13, 2004; revised January 11, 2005; accepted January 13, 2005.

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