Attenuated ischemia-induced neoangiogenesis in BDNF (Val66Met) mutant mice is associated with an enhanced CD36 expression.
L. QIN; R. RATAN; E. KIM; F. S. LEE; S. CHO
Society for Neuroscience. 2008.
Recent studies on the pathophysiology of ischemic stroke suggest that the extent of angiogenesis affects stroke outcome and recovery. In addition to its neuropoietic actions, brain derived neurotrophic factor (BDNF) promotes endothelial cell survival and induces neoangiogenesis in ischemic tissues. A single-nucleotide polymorphism (SNP) in the BDNF gene results in a substitution of methionine (Met) for valine (Val) at codon 66 (Val66Met). The mutation is common in the human population and affects activity-dependent secretion of BDNF. The purpose of this study is to investigate the effect of genetic variant of BDNF (Val66Met) in ischemic outcome and neoangiogeneis in the brain. Male BDNF wild type (Wt: Val/Val) and mutant (Mt: Met/Met) mice were subjected to 30 min middle cerebral artery occlusion using an intraluminal thread method. Intra-ischemic cerebral blood flow was monitored by Laser-Doppler flowmetry before and during ischemia and reperfusion. Infarct volume (IV) and hemispheric swelling assessed 3 days after ischemia revealed no statistical difference between the strains (Wt vs Mt, IV: 36.9Â±4.2, 27.7Â±5.4 mm3; Swelling: 11.5Â±2.7, 7.9Â±3.5%, n=9-15). However, ischemia-induced gene expression of CD36, which has an anti-angiogenic function, was significantly up-regulated in the mutant brain at 3 days (Wt: 2.1Â±0.4; Mt 3.4Â±0.4, n=8-10, p<0.01). In addition, the degree of neoangiogenesis assessed by co-localization of the endothelial cell marker CD31 and cell proliferation marker Ki-67 in the infract area was significantly attenuated in the mutant mice (Wt: 13.6Â±1.3 mm2; Mt: 8.2Â±1.0 mm2, n=3, p<0.05). The results suggest that activity-dependent BDNF secretion is not involved in the development of acute ischemic lesion. Furthermore, an inverse correlation between neoangiogenesis and CD36 gene expression indicates that CD36 plays a role in attenuating ischemia-induced neoangiogenesis in BDNF (Val66Met) mutant mice.