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

Amjad Husain; Arogya Khadka; Allen Ehrlicher; Magali Saint-Geniez; Ramaswamy Krishnan

doi:10.1016/j.bbrc.2021.11.030

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

Biochem Biophys Res Commun. 2022 Jan 1:586:27-33. doi: 10.1016/j.bbrc.2021.11.030. Epub 2021 Nov 13.

Authors

Amjad Husain¹, Arogya Khadka², Allen Ehrlicher³, Magali Saint-Geniez², Ramaswamy Krishnan⁴

Affiliations

¹ Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Innovation and Incubation Centre for Entrepreneurship, IISER, Bhopal, MP, 462066, India; Centre for Science and Society, IISER, Bhopal, MP, 462066, India.
² Schepens Eye Research Institute at Massachusetts Eye and Ear, Boston, MA, 02114, USA.
³ Department of Bioengineering, McGill University, Montreal, H3A0C3, Canada.
⁴ Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. Electronic address: rkrishn2@bidmc.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biomechanical Phenomena
Cell Line
Cell Movement
Cell Proliferation
Elasticity
Endothelial Cells / cytology
Endothelial Cells / metabolism*
Epithelial Cells / cytology
Epithelial Cells / metabolism
Gene Expression Regulation
Humans
Mechanotransduction, Cellular / genetics*
Models, Biological
Neovascularization, Pathologic / genetics
Phosphatidylinositol 3-Kinases / genetics*
Phosphatidylinositol 3-Kinases / metabolism
Primary Cell Culture
Proto-Oncogene Proteins c-akt / genetics*
Proto-Oncogene Proteins c-akt / metabolism
Retinal Pigment Epithelium / cytology
Retinal Pigment Epithelium / metabolism*
TOR Serine-Threonine Kinases / genetics*
TOR Serine-Threonine Kinases / metabolism
Vascular Endothelial Growth Factor A / genetics*
Vascular Endothelial Growth Factor A / metabolism

Substances

VEGFA protein, human
Vascular Endothelial Growth Factor A
MTOR protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding