Delayed rFGF21 Administration Improves Cerebrovascular Remodeling and White Matter Repair After Focal Stroke in Diabetic Mice.

ABSTRACT

Type 2 diabetes mellitus (T2DM) is a major comorbidity exacerbating ischemic brain injury and impairing post-stroke recovery. Our previous study suggested that recombinant human fibroblast growth factor (rFGF) 21 might be a potent therapeutic targeting multiple aspects of pathophysiology in T2DM stroke. This study aims to evaluate the potential effects of rFGF21 on cerebrovascular remodeling after T2DM stroke. Permanent distal middle cerebral artery occlusion was performed in heterozygous non-diabetic db/ + and homozygous diabetic db/db mice. Daily rFGF21 administration was initiated 1 week after stroke induction and maintained for up to 2 weeks thereafter. Multiple markers associated with post-stroke recovery, including angiogenesis, oligodendrogenesis, white matter integrity, and neurogenesis, were assessed up to 3 weeks after stroke. Our results showed an impairment in post-stroke vascular remodeling under T2DM condition, reflected by the decreased expression of trophic factors in brain microvessels and impairments of angiogenesis. The defected cerebrovascular remodeling was accompanied by the decreased oligodendrogenesis and neurogenesis. However, delayed rFGF21 administration normalized post-stroke hyperglycemia and improved neurological outcomes, which may partially be via the promotion of pro-angiogenic trophic factor expression in brain microvessels and cerebrovascular remodeling. The better cerebrovascular remodeling may also contribute to oligodendrogenesis, white matter integrity, and neurogenesis after T2DM stroke. Therefore, delayed rFGF21 administration may improve neurological outcomes in T2DM stroke mice, at least in part by normalizing the metabolic abnormalities and promoting cerebrovascular remodeling and white matter repair.