Abstract: Objective To tested whether the endothelial transient receptor potential cation channel subfamily V member 4 (TRPV4) activation could improve functional recovery in rats subjected to brain ischemia/reperfusion and its mechanisms. Methods 30 SD rats were randomly divided into Sham group, middle cerebral artery occlusion(MCAO)group and 4α-PDD group. The volume of cerebral infarction was detected by TTC method；the degree of nerve injury was evaluated by Garcia score； the expression of endothelial nitric oxide synthase (eNOS), VEGF receptor -2 (VEGFA-2) and vascular endothelial growth factor A (VEGFA) mRNA were detected by quantitative RT-PCR; CD3 and Sox2 proteins were detected by immunohistochemistry. Results Compared with Sham group, the volume of cerebral infarction and neurological deficit in MCAO group increased significantly (P < 0.001). 4α-PDD reduced infarct volume (p < 0.001) and improved functional outcomes (p < 0.05) on day 3 after MCAO.TRPV4 activation significantly increased endothelial nitric oxide synthase(eNOS) expression in the ischemic region(p < 0.001). The expressions of vascular endothelial growth factor A (VEGFA) and VEGF receptor-2 were significantly higher in the 4α-PDD group(p < 0.001). 4α-PDD treatment also caused a significantly increase of microvessel density (p < 0.001). In addition, Neural progenitor cells (NPC) proliferation and migration in the ischemic hemisphere were increased, respectively. Conclusion TRPV4 activation by 4α-PDD may improve functional recovery through angiogenesis and neurogenesis after MCAO.