Abstract
While it is now well-established that substrate stiffness regulates vascular endothelial growth factor-A (VEGF-A) mediated signaling and functions, causal mechanisms remain poorly understood. Here, we report an underlying role for the PI3K/Akt/mTOR signaling pathway. This pathway is activated on stiffer substrates, is amplified by VEGF-A stimulation, and correlates with enhanced endothelial cell (EC) proliferation, contraction, pro-angiogenic secretion, and capillary-like tube formation. In the settings of advanced age-related macular degeneration, characterized by EC and retinal pigment epithelial (RPE)-mediated angiogenesis, these data implicate substrate stiffness as a novel causative mechanism and Akt/mTOR inhibition as a novel therapeutic pathway.
Keywords:
AMD; Angiogenesis; Contraction; Endothelial cell; Proliferation; RPE; Rigidity.
Copyright © 2021 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Biomechanical Phenomena
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Cell Line
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Cell Movement
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Cell Proliferation
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Elasticity
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Endothelial Cells / cytology
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Endothelial Cells / metabolism*
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Epithelial Cells / cytology
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Epithelial Cells / metabolism
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Gene Expression Regulation
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Humans
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Mechanotransduction, Cellular / genetics*
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Models, Biological
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Neovascularization, Pathologic / genetics
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Phosphatidylinositol 3-Kinases / genetics*
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Phosphatidylinositol 3-Kinases / metabolism
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Primary Cell Culture
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Proto-Oncogene Proteins c-akt / genetics*
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Proto-Oncogene Proteins c-akt / metabolism
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Retinal Pigment Epithelium / cytology
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Retinal Pigment Epithelium / metabolism*
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TOR Serine-Threonine Kinases / genetics*
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TOR Serine-Threonine Kinases / metabolism
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Vascular Endothelial Growth Factor A / genetics*
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Vascular Endothelial Growth Factor A / metabolism
Substances
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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MTOR protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases