Substrate stiffening promotes VEGF-A functions via the PI3K/Akt/mTOR pathway

Area of Science:

• Biomedical Engineering
• Cell Biology
• Ophthalmology

Background:

• Substrate stiffness is known to regulate vascular endothelial growth factor-A (VEGF-A) signaling.
• The precise causal mechanisms linking substrate stiffness to VEGF-A functions are not fully understood.

Purpose of the Study:

• To elucidate the underlying mechanisms by which substrate stiffness influences VEGF-A mediated endothelial cell functions.
• To investigate the role of the PI3K/Akt/mTOR signaling pathway in this process.
• To explore potential therapeutic targets for angiogenesis in age-related macular degeneration.

Main Methods:

• Investigated the activation of the PI3K/Akt/mTOR pathway in endothelial cells cultured on substrates of varying stiffness.
• Examined the effect of VEGF-A stimulation on this pathway.
• Assessed endothelial cell proliferation, contraction, pro-angiogenic secretion, and capillary-like tube formation.
• Correlated these findings with disease models of age-related macular degeneration.

Main Results:

• The PI3K/Akt/mTOR signaling pathway is activated by stiffer substrates.
• VEGF-A stimulation amplifies the activation of this pathway.
• Stiffer substrates correlate with enhanced endothelial cell proliferation, contraction, pro-angiogenic secretion, and capillary-like tube formation.
• The pathway's activation is implicated in the angiogenesis observed in age-related macular degeneration.

Conclusions:

• The PI3K/Akt/mTOR pathway plays a critical role in mediating the effects of substrate stiffness on endothelial cells.
• Substrate stiffness represents a novel causative mechanism in angiogenesis associated with age-related macular degeneration.
• Inhibition of Akt/mTOR presents a potential novel therapeutic strategy for treating angiogenesis-driven eye diseases.