Abstract:
C-type natriuretic peptide (CNP) is an important vascular regulator that is present in the brain. Our previous study demonstrated the innate neuroprotectant role of CNP in the neonatal brain after hypoxic-ischemic (HI) insults. In this study, we further explored the role of CNP in cerebrovascular pathology using both in vivo and in vitro models. In a neonatal mouse HI brain injury model, we found that intracerebroventricular administration of recombinant CNP dose-dependently reduces brain infarct size. CNP significantly decreases brain edema and immunoglobulin G (IgG) extravasation into the brain tissue, suggesting a vasculoprotective effect of CNP. Moreover, in primary brain microvascular endothelial cells (BMECs), CNP dose-dependently protects BMEC survival and monolayer integrity against oxygen-glucose deprivation (OGD). The vasculoprotective effect of CNP is mediated by its innate receptors NPR2 and NPR3, in that inhibition of either NPR2 or NPR3 counteracts the protective effect of CNP on IgG leakage after HI insult and BMEC survival under OGD. Of importance, CNP significantly ameliorates brain atrophy and improves neurological deficits after HI insults. Altogether, the present study indicates that recombinant CNP exerts vascular protection in neonatal HI brain injury via its innate receptors, suggesting a potential therapeutic target for the treatment of neonatal HI brain injury.
摘要:
C型利钠肽(CNP)是一种重要的血管调节剂,存在于大脑中。我们先前的研究证明了缺氧缺血性(HI)损伤后CNP在新生儿脑中的先天神经保护作用。在这项研究中,我们使用体内和体外模型进一步探讨了CNP在脑血管病理学中的作用.在新生小鼠HI脑损伤模型中,我们发现,脑室内给药重组CNP剂量依赖性地减少了脑梗死面积.CNP显著减少脑水肿和免疫球蛋白G(IgG)外渗到脑组织,提示CNP的血管保护作用。此外,在原发性脑微血管内皮细胞(BMECs)中,CNP剂量依赖性地保护BMEC存活和单层完整性对抗氧-葡萄糖剥夺(OGD)。CNP的血管保护作用由其先天受体NPR2和NPR3介导,因为NPR2或NPR3的抑制抵消了在OGD下HI损伤和BMEC存活后CNP对IgG渗漏的保护作用。重要的是,CNP可显着改善HI损伤后的脑萎缩并改善神经功能缺损。总之,本研究表明重组CNP通过其固有受体对新生儿HI脑损伤发挥血管保护作用,提示新生儿HI脑损伤的潜在治疗靶点。