期刊
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2022.903047
关键词
hypoxia; senescence; endothelial cells; atomic force microscopy; nano mechanics; hippo pathway
资金
- National Institutes of Health (NIH) [CA78383, CA150190, HL140411]
- Florida Department of Health Cancer Research Chair Fund, Florida [3J]
- Mayo Clinic Pancreatic Cancer Specialized Program of Research Excellence Career Enhancement Award
- Eagles fifth District Cancer Telethon-Cancer Research Fund
- Jay and Deanie Stein Career Development Award for Cancer Research at Mayo Clinic Jacksonville
- 2019 Benefactor Funded Champions for Hope Pancreatic Cancer
- Ed and Ethel Moore Alzheimers Disease Research Program [20A10]
Hypoxia leads to senescence in endothelial cells (ECs), with VEGFR-1 and YAP-1 playing important roles in this process. Senescent ECs exhibit unique morphological and nanomechanical signatures.
Hypoxia-induced endothelial cell (EC) dysfunction has been implicated as potential initiators of different pathogenesis, including Alzheimer's disease and vascular dementia. However, in-depth structural, mechanical, and molecular mechanisms leading to EC dysfunction and pathology need to be revealed. Here, we show that ECs exposed to hypoxic conditions readily enter a senescence phenotype. As expected, hypoxia upregulated the expression of vascular endothelial growth factor (VEGFs) and its receptors (VEGFRs) in the ECs. Interestingly, Knockdown of VEGFR-1 expression prior to hypoxia exposure prevented EC senescence, suggesting an important role of VEGFR-1 expression in the induction of EC senescence. Using atomic force microscopy, we showed that senescent ECs had a flattened cell morphology, decreased membrane ruffling, and increased membrane stiffness, demonstrating unique morphological and nanomechanical signatures. Furthermore, we show that hypoxia inhibited the Hippo pathway Yes-associated protein (YAP-1) expression and knockdown of YAP-1 induced senescence in the ECs, supporting a key role of YAP-1 expression in the induction of EC senescence. And importantly, VEGFR-1 Knockdown in the ECs modulated YAP-1 expression, suggesting a novel VEGFR-1-YAP-1 axis in the induction of hypoxia-mediated EC senescence. In conclusion, VEGFR-1 is overexpressed in ECs undergoing hypoxia-mediated senescence, and the knockdown of VEGFR-1 restores cellular structural and nanomechanical integrity by recovering YAP-1 expression.
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