The Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute and Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Int J Mol Sci. 2021 Aug 20;22(16):8966. doi: 10.3390/ijms22168966.
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.
C 型利钠肽（CNP）是一种存在于大脑中的重要血管调节因子。我们之前的研究表明，CNP 在缺氧缺血（HI）损伤后的新生儿大脑中具有先天的神经保护作用。在这项研究中，我们使用体内和体外模型进一步探索了 CNP 在脑血管病理中的作用。在新生小鼠 HI 脑损伤模型中，我们发现脑室内给予重组 CNP 可剂量依赖性地减少脑梗死面积。CNP 可显著降低脑水肿和免疫球蛋白 G（IgG）向脑组织的渗出，表明 CNP 具有血管保护作用。此外，在原代脑微血管内皮细胞（BMEC）中，CNP 可剂量依赖性地保护 BMEC 存活和单层完整性免受氧葡萄糖剥夺（OGD）的影响。CNP 的血管保护作用是通过其先天受体 NPR2 和 NPR3 介导的，因为抑制 NPR2 或 NPR3 均可拮抗 CNP 对 HI 损伤后 IgG 渗漏和 OGD 下 BMEC 存活的保护作用。重要的是，CNP 可显著改善 HI 损伤后的脑萎缩和神经功能缺损。总之，本研究表明，重组 CNP 通过其先天受体发挥对新生 HI 脑损伤的血管保护作用，提示其可能成为治疗新生儿 HI 脑损伤的潜在治疗靶点。
