Hypoxia-activated microglia promote pathological angiogenesis via an FN/ITGB3/FAK/Akt pathway
5 affiliations
- 1Department of Ophthalmology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
- 2Beijing Collaborative Innovation Centre for Cardiovascular Disorders, the Key Laboratory of Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
- 3Department of Vascular Surgery, Beijing Luhe Hospital, Capital Medical University, Beijing 101100, China
- 4Department of Ophthalmology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
- 5Xiamen Eye Center and Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, Fujian Province, China
Abstract
AIM: To investigate whether hypoxia-activated microglia drive pathological neovascularization through extracellular matrix (ECM) remodeling and endothelial integrin signaling, a mechanism that may function in parallel with vascular endothelial growth factor (VEGF) signaling. METHODS: The oxygen-induced retinopathy (OIR) mouse model was used. Retinal phenotypes were assessed by flat mounts, histology, and vascular leakage assays. Key pathways were screened by transcriptomics and validated via Western blot, immunofluorescence, and quantitative polymerase chain reaction (qPCR). In vitro, brain microvascular endothelial cells were treated with conditioned medium from hypoxic microglia (Hyp-CM), with cell migration and tube formation assessed. Interventions employed the integrin β3 (ITGB3) inhibitor cilengitide, the focal adhesion kinase (FAK) inhibitor PF-573228 and a neutralizing anti-VEGF antibody. In vivo, cilengitide was administered by intravitreal injection to evaluate its therapeutic effect on neovascularization. RESULTS: OIR retinas showed significant avascularity, pathological neovascularization, and barrier disruption. Transcriptomics revealed activation of ECM-receptor interaction and focal adhesion pathways, with upregulation of Fn1 and Itgb3. Increased protein levels of fibronectin (FN) and ITGB3, alongside elevated phosphorylation of FAK and protein kinase B (Akt), were confirmed in vivo. Activated microglia co-localized with upregulated FN and ITGB3. Conditioned medium from Hyp-CM activated the ITGB3–FAK–Akt pathway in endothelial cells and promoted their migration and tube formation. These effects were nearly abolished by cilengitide or PF-573228. VEGF neutralization partially reduced Hyp-CM-induced migration and tube formation. Intravitreal injection of cilengitide significantly reduced retinal neovascularization in OIR mice. CONCLUSION: Hypoxia-activated microglia promote pathological angiogenesis, and the FN/ITGB3/FAK/Akt axis is identified as a key mediator of this process, revealing a novel mechanism that operates in parallel with VEGF signaling. Targeting this “hypoxia–microglia–ECM–integrin” axis represents a promising therapeutic strategy to overcome anti-VEGF resistance in ischemic retinopathy.
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BibTeX
@article{hao2026hypoxiaactivated,
title = {{Hypoxia-activated microglia promote pathological angiogenesis via an FN/ITGB3/FAK/Akt pathway}},
author = {Lan-Cao Hao and De-Hui Li and Kun Zhang and Chen-Zi Liu and Ming-Hao Sun and Xin-Xiao Gao and Si-Quan Zhu},
journal = {International Journal of Ophthalmology},
year = {2026},
month = nov,
doi = {10.18240/ijo.2026.11.02},
url = {https://doi.org/10.18240/ijo.2026.11.02},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Hypoxia-activated microglia promote pathological angiogenesis via an FN/ITGB3/FAK/Akt pathway
AU - Lan-Cao Hao
AU - De-Hui Li
AU - Kun Zhang
AU - Chen-Zi Liu
AU - Ming-Hao Sun
AU - Xin-Xiao Gao
AU - Si-Quan Zhu
PY - 2026
DA - 2026/11/02
JO - International Journal of Ophthalmology
DO - 10.18240/ijo.2026.11.02
UR - https://doi.org/10.18240/ijo.2026.11.02
AB - AIM: To investigate whether hypoxia-activated microglia drive pathological neovascularization through extracellular matrix (ECM) remodeling and endothelial integrin signaling, a mechanism that may function in parallel with vascular endothelial growth factor (VEGF) signaling. METHODS: The oxygen-induced retinopathy (OIR) mouse model was used. Retinal phenotypes were assessed by flat mounts, histology, and vascular leakage assays. Key pathways were screened by transcriptomics and validated via Western blot, immunofluorescence, and quantitative polymerase chain reaction (qPCR). In vitro, brain microvascular endothelial cells were treated with conditioned medium from hypoxic microglia (Hyp-CM), with cell migration and tube formation assessed. Interventions employed the integrin β3 (ITGB3) inhibitor cilengitide, the focal adhesion kinase (FAK) inhibitor PF-573228 and a neutralizing anti-VEGF antibody. In vivo, cilengitide was administered by intravitreal injection to evaluate its therapeutic effect on neovascularization. RESULTS: OIR retinas showed significant avascularity, pathological neovascularization, and barrier disruption. Transcriptomics revealed activation of ECM-receptor interaction and focal adhesion pathways, with upregulation of Fn1 and Itgb3. Increased protein levels of fibronectin (FN) and ITGB3, alongside elevated phosphorylation of FAK and protein kinase B (Akt), were confirmed in vivo. Activated microglia co-localized with upregulated FN and ITGB3. Conditioned medium from Hyp-CM activated the ITGB3–FAK–Akt pathway in endothelial cells and promoted their migration and tube formation. These effects were nearly abolished by cilengitide or PF-573228. VEGF neutralization partially reduced Hyp-CM-induced migration and tube formation. Intravitreal injection of cilengitide significantly reduced retinal neovascularization in OIR mice. CONCLUSION: Hypoxia-activated microglia promote pathological angiogenesis, and the FN/ITGB3/FAK/Akt axis is identified as a key mediator of this process, revealing a novel mechanism that operates in parallel with VEGF signaling. Targeting this “hypoxia–microglia–ECM–integrin” axis represents a promising therapeutic strategy to overcome anti-VEGF resistance in ischemic retinopathy.
SN - 2222-3959
SN - 2227-4898
ER -