title: Genetic variant of BDNF (Val66Met) polymorphism attenuates stroke-induced angiogenic responses by enhancing anti-angiogenic mediator CD36 expression.
abstract: Brain-derived neurotrophic factor (BDNF) has been shown to be necessary and sufficient for post-stroke recovery in rodents. From these observations, we and others have hypothesized that a common single nucleotide polymorphism (SNP) in the pro-domain of bdnf that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) will affect stroke outcome. Here we investigate the effect of the BDNF genetic variant on ischemic outcome by using mice with a genetic knock-in of the human BDNF variant in both alleles (BDNF(Met/Met)). Compared with wild-type mice, BDNF(Met/Met) mice exhibited reduced CNS BDNF levels without a discernable effect on infarct size. Diminished BDNF levels in BDNF(Met/Met) mice were associated with greater deficits in post-stroke locomotor functions. Additionally, the BDNF(Met/Met) mice showed reduced angiogenesis and elevated expression of thrombospondin-1 (TSP-1) and its receptor CD36, anti-angiogenic factors. To assess the functional role of CD36 in antagonizing angiogenic response in Met homozygosity at the BDNF locus, we crossed BDNF(Met/Met) mice with CD36 knock-out mice. The double-mutant mice rescued the angiogenic deficit associated with the BDNF(Met/Met) mice without alterations in BDNF levels, indicating that the behavioral deficit in BDNF(Met/Met) mice after stroke is partly related to an unfavorable balance in pro-angiogenic BDNF and anti-angiogenic TSP-1/CD36. The results suggest that CD36 inhibition may be a viable strategy to enhance angiogenesis and possible recovery in human stroke victims who are Met homozygotes at codon 66 of the BDNF locus.
authors.affiliation: Burke-Cornell Medical Research Institute, White Plains, New York 10605, USA.
authors.forename: Luye
authors.initials: L
authors.lastname: Qin
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.forename: Rajiv
authors.initials: R
authors.lastname: Ratan
authors.forename: Francis S
authors.initials: FS
authors.lastname: Lee
authors.forename: Sunghee
authors.initials: S
authors.lastname: Cho
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000473:pathology; D020520:Brain Infarction / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D018955:CD36 Antigens / Q000096:biosynthesis*; D002560:Cerebrovascular Circulation; D042783:Endothelial Cells / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity; D018919:Neovascularization, Physiologic; D020641:Polymorphism, Single Nucleotide; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D019700:Thrombospondin 1 / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018955:CD36 Antigens; D019700:Thrombospondin 1