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Aims: SUMOylation is a posttranslational modification related to multiple human diseases. SUMOylation can be reversed by classes of proteases known as the sentrin/SUMO‐specific proteases (SENPs). In the present study, we investigate the potential role of SENP1 in pericytes in the brain ischemia. Methods: Pericyte‐specific deletion of senp1 mice (Cspg4‐Cre; senp1f/f) were used for brain function and neuronal damage evaluation following brain ischemia. The cerebral blood vessels of diameter, velocity, and flux were performed in living mice by two‐photon laser scanning microscopy (TPLSM). Biochemical analysis and immunohistochemistry methods were used to address the role and mechanism of pericyte‐specific SENP1 in the pathological process of brain ischemia. A coculture model of HBVPs and HBMECs mimicked the BBB in vitro and was used to evaluate BBB integrity after glucose deprivation. Results: Our results showed that senp1‐specific deletion in pericytes did not affect the motor function and cognitive function of mice. However, the pericyte‐specific deletion of senp1 aggravated the infarct size and motor deficit following focal brain ischemia. Consistently, the TPLSM data demonstrated that SENP1 deletion in pericytes accelerated thrombosis formation in brain microvessels. We also found that pericyte‐specific deletion of senp1 exaggerated the neuronal damage significantly following brain ischemia in mice. Moreover, SENP1 knockdown in pericytes could activate the apoptosis signaling and disrupt the barrier integrity in vitro coculture model. Conclusions: Our findings revealed that targeting SENP1 in pericytes may represent a novel therapeutic strategy for neurovascular protection in stroke. [ABSTRACT FROM AUTHOR]