C-Type Natriuretic Peptide Ameliorates Vascular Injury and Improves Neurological Outcomes in Neonatal Hypoxic-Ischemic Brain Injury in Mice.

Guofang Shen,Zhen Zhao,Shirley Hu,Qingyi Ma,Lubo Zhang

doi:10.3390/ijms22168966

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.

Highlights

Hypoxic-ischemic (HI) events such as birth asphyxia induce neonatal brain injury that initiates shortly after HI insults and develops over days [1,2]
We evaluated whether NPR2 and NPR3 mediated the cytoprotective effect of C-type natriuretic peptide (CNP) on primary brain endothelial cells during oxygen-glucose deprivation (OGD)
We found that blood–brain barrier (BBB) disruption evidenced by brain edema and immunoglobulin G (IgG) extravasation was present in pups 24 h after HI insults

Summary

Introduction

Hypoxic-ischemic (HI) events such as birth asphyxia induce neonatal brain injury that initiates shortly after HI insults and develops over days [1,2]. Previous studies revealed that blood–brain barrier (BBB) impairment occurs within hours after neonatal HI brain injury and may contribute to disease progression [3,4,5]. Multiple factors such as oxidative stress, nitrosative stress, and inflammation contribute to endothelial dysfunction and tight junction breakdown, which increase the risk of vasogenic edema and hemorrhage [6,7]. It is found that cerebral edema is closely associated with severe cases of HIE and worse neurological outcomes [4,10,11,12] These findings suggest that BBB protection and brain edema reduction are potential strategies in the treatment of neonatal

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