Lizhen Fan1  · Hui Liu3  · Shanshan Li1  · Lingling Li1  · Zhi Zhang2,4,5,6,7 · Pinyi Liu2,4,5,6,7 · Haiyan Yang2,4,5,6,7 · Shengnan Xia2,4,5,6,7 · Xiang Cao2,4,5,6,7  · Chun Wang1  · Yun Xu2,4,5,6,7

1 Department of Geriatrics, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China 

2 Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China 

3 Department of Pharmacy, The Second Hospital of Nanjing, Affiliated Hospital to Nanjing University of Chinese Medicine, Nanjing 210000, China 

4 Jiangsu Key Laboratory for Molecular Medicine and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing 210008, China 

5 Nanjing Neurology Clinical Medical Center, Nanjing 210008, China 

6 The Brain Disease and Brain Science Center of Nanjing Drum Tower Hospital, Nanjing 210008, China 

7 Nanjing Key Laboratory for Cardiovascular Information and Health Engineering Medicine, Nanjing 210008, China

Abstract

Blood-brain barrier (BBB) dysfunction represents a critical pathological manifestation in exacerbating ischemic stroke, contributing to neuronal death, edema formation, and unfavorable clinical outcomes. GATA zinc finger domain-containing 1 (GATAD1) is recognized as a critical transcription factor in cardiac development and cardiovascular disease. However, the role of GATAD1 in regulating BBB function and ischemic stroke remains elusive. Here, we found that GATAD1 was upregulated in cerebral endothelial cells (ECs) following ischemic stroke in mice. EC-specific Gatad1 deficiency demonstrated remarkable neuroprotection, manifested by reduced infarct volumes, ameliorated BBB dysfunction, and improved neurological outcomes following experimental stroke. Mechanistic investigations revealed that GATAD1 was involved in regulating CD36 expression, thereby modulating caveolae-mediated transcytosis in cerebral ECs. These findings established GATAD1 as a novel regulator of BBB permeability and a potential therapeutic target for ischemic stroke intervention.

Keywords

GATAD1; Blood-brain barrier; Transcytosis; Ischemic stroke

[SpringerLink]