Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China.
Research Laboratory for Biomedical Optics and Molecular Imaging, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
CNS Neurosci Ther. 2020 Aug;26(8):815-828. doi: 10.1111/cns.13398. Epub 2020 Jun 4.
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.
Pericyte-specific deletion of senp1 mice (Cspg4-Cre; senp1 ) 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.
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.
Our findings revealed that targeting SENP1 in pericytes may represent a novel therapeutic strategy for neurovascular protection in stroke.
SUMO 化是一种与多种人类疾病相关的翻译后修饰。SUMO 化可以通过一类称为 sentrin/SUMO 特异性蛋白酶（SENP）的蛋白酶逆转。在本研究中，我们研究了 SENP1 在脑缺血中的周细胞中的潜在作用。
使用周细胞特异性缺失 senp1 小鼠（Cspg4-Cre; senp1 ）评估脑缺血后大脑功能和神经元损伤。通过双光子激光扫描显微镜（TPLSM）在活体小鼠中进行脑血管直径、速度和通量的测量。生物化学分析和免疫组织化学方法用于解决周细胞特异性 SENP1 在脑缺血病理过程中的作用和机制。HBVPs 和 HBMECs 的共培养模型模拟了体外 BBB，并用于评估葡萄糖剥夺后 BBB 的完整性。
我们的结果表明，周细胞中特异性缺失 senp1 不会影响小鼠的运动功能和认知功能。然而，周细胞特异性缺失 senp1 加重了局灶性脑缺血后的梗死面积和运动缺陷。一致地，TPLSM 数据表明，周细胞中 SENP1 的缺失加速了脑微血管中的血栓形成。我们还发现，周细胞中特异性缺失 senp1 显著加重了脑缺血后小鼠的神经元损伤。此外，周细胞中 SENP1 的敲低可在体外共培养模型中激活凋亡信号并破坏屏障完整性。
我们的研究结果表明，针对周细胞中的 SENP1 可能代表了中风中神经血管保护的一种新的治疗策略。
