Matrix stiffness regulates vascular integrity through focal adhesion kinase activity

Area of Science:

• Biomedical Engineering
• Cancer Biology
• Vascular Biology

Background:

• Tumor vasculature exhibits increased permeability compared to healthy tissue, potentially driving aggressive tumor phenotypes and hindering drug delivery.
• While tumor matrix stiffening is linked to increased vascular permeability, the underlying molecular mechanisms are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms by which extracellular matrix stiffening influences endothelial barrier function.
• To determine the role of focal adhesion kinase (FAK) in matrix stiffness-mediated vascular permeability.
• To explore FAK as a potential therapeutic target for enhancing vascular integrity in tumors.

Main Methods:

• Utilized an in vitro model of tumor stiffening (ex ovo culture) and a mouse model.
• Investigated the effects of pharmaceutical inhibition of FAK on endothelial permeability.
• Analyzed Src localization to cell-cell junctions and vascular endothelial cadherin phosphorylation.

Main Results:

• Increased matrix stiffness elevates endothelial permeability, an effect preventable by FAK inhibition both in vitro and ex ovo.
• Matrix stiffness-mediated FAK activation promotes Src localization to cell-cell junctions, leading to increased vascular endothelial cadherin phosphorylation.
• Endothelial cells in stiff tumors show higher Src activity and vascular endothelial cadherin phosphorylation at adherens junctions compared to those in compliant tumors.

Conclusions:

• Matrix stiffness regulates endothelial barrier integrity through FAK activity, elucidating a key mechanism of extracellular matrix influence on vascular function.
• FAK plays a critical role in maintaining endothelial barrier integrity, highlighting its potential as a therapeutic target in cancer treatment.