Endothelial αvβ3 integrin induction during hypoxia protects blood-brain barrier integrity

• 成果类型: Article
• 署名作者: Halder, Sebok K.; Delorme-Walker, Violaine D.; Milner, Richard
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9594
• DOI: 10.1073/pnas.2510931122
• 发表日期: 2025-09-17
• 关键词: alpha-5-beta-1 integrin; vascular cells; alpha(v)beta(3); angiogenesis; mice; proliferation; microvessels; adhesion; vessels; absence

摘要

The blood-brain barrier (BBB) is critical for maintaining cerebral homeostasis, and its deterioration with age is an important pathogenic factor in the etiology of vascular dementia. Extracellular matrix-integrin interactions play a central role in regulating vascular stability.The alpha v beta 3 integrin is not expressed by brain endothelial cells under stable conditions but is strongly induced by hypoxia. However, it is currently unclear whether alpha v beta 3 integrin exerts a destructive or protective influence on BBB integrity. In young (8 to 10 wk) and aged (20 mo) mice, we examined the impact of a function-blocking beta 3 integrin antibody as well as the inhibitory peptide cilengitide on BBB disruption during exposure to CMH (8% O2). Hypoxic induction of brain endothelial beta 3 integrin was much stronger in aged mice. In both young and aged mice, beta 3 integrin inhibition greatly amplified hypoxia-induced BBB disruption, correlating with loss of tight junction proteins and induction of the leaky BBB marker mouse endothelial cell antigen (MECA)-32. Consistent with this, beta 3 integrin null mice showed increased levels of hypoxia-induced BBB disruption and MECA-32 expression. Cilengitide also reduced the integrity of a brain endothelial monolayer in vitro, prevented beta 3 integrin localization to focal adhesions, and reduced expression of vascular endothelial (VE)-cadherin and tight junction proteins. These observations suggest that hypoxic induction of endothelial alpha v beta 3 integrin enhances BBB integrity by stabilizing endothelial adhesion. This raises the interesting possibility that pharmacological upregulation of endothelial alpha v beta 3 integrin in the aged brain might hold therapeutic promise for vascular dementia.