Acute,not delayed,treatment of aflibercept enhances vessel density in post-ischemic brain and promotes long-term stroke recovery in obese mice

Abstract

Vascular comorbidities complicate stroke pathophysiology, worsen outcomes, and delay recovery. Obesity, in particular, significantly increases stroke-induced brain edema, a fatal complication during infarction, which leads to worsened long-term recovery. Treatment of aflibercept, a VEGF-trap, has been shown to reduce stroke-induced brain edema and attenuate acute neurological deficits in obese mice. However, the effect of aflibercept on long-term stroke recovery is unknown. We found that treating obese stroke mice with aflibercept at 3 hours displayed significantly improved long-term motor and cognitive function. Notably, VEGFR2 expression was upregulated at 3- and 7-days post-stroke, indicating sustained VEGF signaling in obese subjects. Unlike acute treatment of aflibercept at 3 hours post-stroke, delayed treatment (3-day) worsened stroke recovery. While the improved long-term stroke recovery in mice treated aflibercept 3 hours is associated with the upregulated Pecam-1 and Angiopoietin-1 mRNAs and vessel densities in peri-infarct area at 3 months post-stroke, the delayed treatment led to a reduction in both angiogenic marker expression and vessel density. These findings highlight the importance of early intervention with VEGF signaling in obese mice to promote subsequent vascular remodeling during the stroke recovery phase and indicate a critical therapeutic window for VEGF inhibition to treat stroke in subjects with vascular comorbidities.