TGFα plays essential roles in angiogenesis and cognitive recovery after ischemic stroke

Stroke is a major global health issue and imposes a financial burden on both survivors and caregivers. Current treatments for ischemic stroke, such as intravenous thrombolysis and endovascular thrombectomy, have strict time constraints, leaving a substantial need for therapies that improve tissue recovery. Enhancing revascularization is essential for creating a supportive environment for brain repair. Our previous study shows that transforming growth factor alpha (TGFα) is critical in promoting white matter integrity and long-term recovery by protecting oligodendrocytes after stroke. We detected the expression of epidermal growth factor receptor (EGFR), a receptor of TGFα, along brain blood vessels, however its role in post-stroke vasculature remains unexplored. Here, we used TGFα knockout (KO) mouse and wild-type controls to examine the role of TGFα in post-stroke angiogenesis and cognitive function recovery. Immunofluorescence quantification revealed that TGFα KO mice showed significantly lower endothelial cell (EC) proliferation and angiogenesis, as revealed by the reduced numbers of Ki67⁺CD31⁺ cells and BrdU⁺CD31⁺ cells, respectively. Behavioral tests demonstrated increased cognitive deficits in the TGFα KO group, correlating with the decreased angiogenesis. Additionally, in vitro studies using primary mouse brain microvascular endothelial cells (mBMECs) confirmed that TGFα directly enhanced EC proliferation and formation of tubular structure. TGFα also promoted EC wound healing, which relied on the activation of EGFR signaling. Collectively, these results indicate that TGFα supports endothelial network formation and vascular recovery, highlighting its therapeutic potential to promote revascularization and improve cognitive functions after ischemic stroke.