Stroke is a major cause of neurological disability and death, but most patients improve over weeks to months after stroke, suggesting that endogenous mechanisms exist for limiting and reversing the effects of brain ischemia. These include neuroprotection, which prevents the progression of reversible to irreversible injury, and neuroregeneration, which replaces lost cells, circuits and functions. In previous work supported by this grant, we found that vascular endothelial growth factor (VEGF, or VEGFA) protects neurons from hypoxia in vitro and ischemia in vivo, promotes adult neurogenesis, improves histological and functional outcome after experimental stroke, and stimulates neurite outgrowth. These effects are mediated largely through the VEGFR2 receptor, although we have also found that VEGFB, which acts via VEGFR1, has some of the same actions. Other endogenous VEGF family members-VEGFC, VEGFD, and placental growth factor (PlGF)- have different receptor specificities, and little is known about their effects on the nervous system. We propose to continue our study of VEGF effects on neuroprotection, neurogenesis and recovery after stroke, based on the hypothesis that different VEGF family members operate via distinct but overlapping signaling pathways to regulate diverse aspects of ischemic neuroprotection, ischemia-induced neurogenesis, and post-ischemic recovery. This hypothesis will be tested by addressing the following specific aims: (1) Compare the neuroprotective and neurogenesis-promoting effects of VEGFB and VEGFC;(2) Evaluate the ability of VEGFB and VEGFC to enhance repair and recovery in the post-acute phase following experimental stroke;(3) Identify the signal transduction pathways employed in the neuroprotective and neurogenesis-promoting effects of VEGFB and VEGFC;and (4) Determine the contribution of endothelial cells to the neuroprotective and neurogenesis-promoting effects of VEGFB and VEGFC.

Public Health Relevance

In previous work supported by this grant, we found that vascular endothelial growth factor (VEGF, or VEGFA) protects neurons from oxygen deprivation and brain ischemia, promotes the production of new neurons (neurogenesis), improves outcome after experimental stroke, and stimulates outgrowth of nerve processes (neurites). We propose to continue our study of VEGF effects on neuroprotection, neurogenesis and recovery after stroke, based on the hypothesis that different VEGF family members (VEGFB and VEGFC) operate via distinct but overlapping signaling pathways to regulate ischemic neuroprotection, ischemia-induced neurogenesis, and post-ischemic recovery. The proposed studies will help to delineate the potential and limitations of VEGF family members in the treatment of stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044921-10
Application #
8530051
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Owens, David F
Project Start
2002-12-15
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$401,332
Indirect Cost
$194,460
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945
Xie, Lin; Mao, Xiaoou; Jin, Kunlin et al. (2013) Vascular endothelial growth factor-B expression in postischemic rat brain. Vasc Cell 5:8
Tang, Huidong; Mao, XiaoOu; Xie, Lin et al. (2013) Expression level of vascular endothelial growth factor in hippocampus is associated with cognitive impairment in patients with Alzheimer's disease. Neurobiol Aging 34:1412-5
Greenberg, David A (2013) Preclinical stroke research: gains and gaps. Stroke 44:S114-5
Greenberg, David A; Jin, Kunlin (2013) Vascular endothelial growth factors (VEGFs) and stroke. Cell Mol Life Sci 70:1753-61
Jin, Kunlin; Xie, Lin; Sun, Fen et al. (2011) Corpus callosum and experimental stroke: studies in callosotomized rats and acallosal mice. Stroke 42:2584-8
Jin, Kunlin; Xie, Lin; Mao, XiaoOu et al. (2011) Effect of human neural precursor cell transplantation on endogenous neurogenesis after focal cerebral ischemia in the rat. Brain Res 1374:56-62
Jin, Kunlin; Wang, Xiaomei; Xie, Lin et al. (2010) Transgenic ablation of doublecortin-expressing cells suppresses adult neurogenesis and worsens stroke outcome in mice. Proc Natl Acad Sci U S A 107:7993-8
Jin, Kunlin; Mao, Xiaoou; Xie, Lin et al. (2010) Delayed transplantation of human neural precursor cells improves outcome from focal cerebral ischemia in aged rats. Aging Cell 9:1076-83
Lai, Bin; Mao, Xiao Ou; Xie, Lin et al. (2010) Electrophysiological properties of subventricular zone cells in adult mouse brain. Brain Res 1340:96-105
Jin, Kunlin; Mao, Xiaoou; Xie, Lin et al. (2010) Transplantation of human neural precursor cells in Matrigel scaffolding improves outcome from focal cerebral ischemia after delayed postischemic treatment in rats. J Cereb Blood Flow Metab 30:534-44

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