Matrix Resistance Toward Proteolytic Cleavage Controls Contractility-Dependent Migration Modes During Angiogenic...

Area of Science:

• Biomedical Engineering
• Cell Biology
• Biomaterials Science

Background:

• Angiogenesis, the formation of new blood vessels, is crucial for tissue homeostasis and disease.
• The extracellular matrix (ECM) physically regulates cell behavior, but its role in endothelial cell migration during angiogenesis is not fully understood.
• Physical cues like matrix stiffness and degradability are known regulators, yet the impact of matrix resistance on migration phenotype remains unexplored.

Purpose of the Study:

• To investigate how physical cues from the extracellular matrix regulate endothelial cell migration during angiogenic sprouting.
• To explore the relationship between matrix resistance and endothelial cell migration modes.
• To elucidate the role of cytoskeletal remodeling in response to matrix properties.

Main Methods:

• Development of a biomimetic model using a tunable synthetic hydrogel for angiogenic sprouting.
• Systematic variation of matrix crosslinking density, degradability, and cellular proteolytic activity.
• Analysis of endothelial cell migration phenotypes and actin cytoskeleton organization.

Main Results:

• Endothelial cells sense and respond to the resistance of the ECM towards proteolytic cleavage.
• Matrix resistance, influenced by crosslinking, degradability, and cell proteolysis, dictates migration strategy.
• High matrix resistance induces a switch from collective to single-cell migration, dependent on actomyosin contractility.
• This migration switch is associated with significant actin cytoskeleton reorganization, including loss of stress fibers and formation of punctate F-actin clusters.

Conclusions:

• Matrix resistance is a novel regulator of angiogenic sprouting.
• Physical properties of the ECM significantly impact endothelial cell migration modes via cytoskeletal remodeling.
• Findings provide a new mechanism linking the biophysical microenvironment to cell migration dynamics in angiogenesis.