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

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. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

The study reveals the underlying role of the PI3K/Akt/mTOR signaling pathway in regulating vascular endothelial growth factor-A (VEGF-A) mediated signaling and functions. The pathway is activated on stiffer substrates, amplified by VEGF-A stimulation, and correlated with enhanced endothelial cell (EC) proliferation, contraction, pro-angiogenic secretion, and capillary-like tube formation. These findings have important implications for understanding age-related macular degeneration and provide insight into potential therapeutic pathways.