Endothelial-Specific Deficiency of ATG5 (Autophagy Protein 5) Attenuates Ischemia-Related Angiogenesis
Publikation: Beitrag in Fachzeitschrift › Forschungsartikel › Beigetragen › Begutachtung
Beitragende
Abstract
Objective-Pathological angiogenesis, such as exuberant retinal neovascularization during proliferative retinopathies, involves endothelial responses to ischemia/hypoxia and oxidative stress. Autophagy is a clearance system enabling bulk degradation of intracellular components and is implicated in cellular adaptation to stressful conditions. Here, we addressed the role of the ATG5 (autophagy-related protein 5) in endothelial cells in the context of pathological ischemia-related neovascularization in the murine model of retinopathy of prematurity. Approach and Results-Autophagic vesicles accumulated in neovascular tufts of the retina of retinopathy of prematurity mice. Endothelium-specific Atg5 deletion reduced pathological neovascularization in the retinopathy of prematurity model. In contrast, no alterations in physiological retina vascularization were observed in endothelial-specific ATG5 deficiency, suggesting a specific role of endothelial ATG5 in pathological hypoxia/reoxygenation-related angiogenesis. Consistently, in an aortic ring angiogenesis assay, endothelial ATG5 deficiency resulted in impaired angiogenesis under hypoxia/reoxygenation conditions. As compared to ATG5-sufficient endothelial cells, ATG5-deficient cells displayed impaired mitochondrial respiratory activity, diminished production of mitochondrial reactive oxygen species and decreased phosphorylation of the VEGFR2 (vascular endothelial growth factor receptor 2). Consistently, ATG5-deficient endothelial cells displayed decreased oxidative inactivation of PTPs (phospho-Tyrosine phosphatases), likely due to the reduced reactive oxygen species levels resulting from ATG5 deficiency. Conclusions-Our data suggest that endothelial ATG5 supports mitochondrial function and proangiogenic signaling in endothelial cells in the context of pathological hypoxia/reoxygenation-related neovascularization. Endothelial ATG5, therefore, represents a potential target for the treatment of pathological neovascularization-Associated diseases, such as retinopathies.
Details
Originalsprache | Englisch |
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Seiten (von - bis) | 1137-1148 |
Seitenumfang | 12 |
Fachzeitschrift | Arteriosclerosis, thrombosis, and vascular biology |
Jahrgang | 39 |
Ausgabenummer | 6 |
Publikationsstatus | Veröffentlicht - 1 Juni 2019 |
Peer-Review-Status | Ja |
Externe IDs
PubMed | 31070476 |
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ORCID | /0000-0001-7803-1972/work/142235100 |
Schlagworte
ASJC Scopus Sachgebiete
Schlagwörter
- autophagy-related protein 5, endothelium, mitochondria, oxidative stress, retinal neovascularization