Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke.
Vascular endothelial growth factor (VEGF), an angiogenic factor produced in response to ischemic injury, promotes vascular permeability (VP). Evidence is provided that Src kinase regulates VEGF-mediated VP in the brain following stroke and that suppression of Src activity decreases VP thereby minimizing brain injury. Mice lacking pp60c-src are resistant to VEGF-induced VP and show decreased infarct volumes after stroke whereas mice deficient in pp59c-fyn, another Src family member, have normal VEGF-mediated VP and infarct size. Systemic application of a Src-inhibitor given up to six hours following stroke suppressed VP protecting wild-type mice from ischemia-induced brain damage without influencing VEGF expression. This was associated with reduced edema, improved cerebral perfusion and decreased infarct volume 24 hours after injury as measured by magnetic resonance imaging and histological analysis. Thus, Src represents a key intermediate and novel therapeutic target in the pathophysiology of cerebral ischemia where it appears to regulate neuronal damage by influencing VEGF-mediated VP.
Paul
R
R
Departments of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California, USA.
Zhang
Z G
ZG
Eliceiri
B P
BP
Jiang
Q
Q
Boccia
A D
AD
Zhang
R L
RL
Chopp
M
M
Cheresh
D A
DA
D000818:Animals; D001921:Brain / Q000098:blood supply; D001930:Brain Injuries / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability; D002544:Cerebral Infarction / Q000473:pathology; D004487:Edema / Q000473:pathology; D016228:Endothelial Growth Factors / Q000235:genetics; D015870:Gene Expression; D008222:Lymphokines / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012039:Regional Blood Flow; D020521:Stroke / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019061:src-Family Kinases