TY - JOUR
T1 - Vascular Endothelial Growth Factor Receptor-1 Modulates Hypoxia-Mediated Endothelial Senescence and Cellular Membrane Stiffness via YAP-1 Pathways
AU - Angom, Ramcharan Singh
AU - Kulkarni, Tanmay
AU - Wang, Enfeng
AU - Kumar Dutta, Shamit
AU - Bhattacharya, Santanu
AU - Das, Pritam
AU - Mukhopadhyay, Debabrata
N1 - Publisher Copyright:
Copyright © 2022 Angom, Kulkarni, Wang, Kumar Dutta, Bhattacharya, Das and Mukhopadhyay.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - 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.
AB - 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.
KW - atomic force microscopy
KW - endothelial cells
KW - hippo pathway
KW - hypoxia
KW - nano mechanics
KW - senescence
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U2 - 10.3389/fcell.2022.903047
DO - 10.3389/fcell.2022.903047
M3 - Article
AN - SCOPUS:85134213678
SN - 2296-634X
VL - 10
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
M1 - 903047
ER -