Delta like 4 regulates cerebrovascular development and endothelial integrity via DLL4‐NOTCH‐CLDN5 pathway and is vulnerable to neonatal hyperoxia

• DOI: 10.1113/jp285716
• Publication Date: 2024-04-18T05:33:46Z
• Authors: Xingrao Ke; Sheng Xia; Wei Yu; Sherry Mabry; Qi Fu; Heather L. Menden; Venkatesh Sampath; Robert H. Lane
• Keywords: Hyperoxia

Abstract The mechanisms governing brain vascularization during development remain poorly understood. A key regulator of developmental is delta like 4 (DLL4), a Notch ligand prominently expressed in endothelial cells (EC). Exposure to hyperoxia premature infants can disrupt the and functions cerebral blood vessels lead long‐term cognitive impairment. However, its role vascular impact postnatal on DLL4 expression mouse EC have not been explored. We determined pattern downstream signalling gene using Dll4 +/+ +/LacZ mice. also performed vitro studies human microvascular cells. Finally, we Cldn5 exposed hyperoxia. various cell types, with being predominant one immature brains. Moreover, deficiency leads persistent abnormalities microvasculature increased permeability both vivo . identified that insufficiency compromises integrity through NOTCH‐NICD‐RBPJ‐CLDN5 pathway, resulting downregulation tight junction protein claudin 5 (CLDN5). exposure neonatal reduces CLDN5 developing EC. reveal indispensable for maintaining blood–brain barrier's function repressed by speculate reduced may contribute impaired observed neonates image Key points cells, remains unknown. demonstrate at high level brains abnormal vasculature increases identify regulates signalling. are decreased