SVEP1 influences monocyte to macrophage differentiation via integrin α4β1/α9β1 and Rho/Rac signalling

Area of Science:

• Cardiovascular Biology
• Extracellular Matrix Research
• Cellular Adhesion Mechanisms

Background:

• The extracellular matrix protein SVEP1 mediates cell adhesion through integrin α9β1.
• A SVEP1 variant is associated with increased coronary artery disease (CAD) risk.
• SVEP1's role in CAD pathogenesis, particularly in monocyte recruitment and differentiation, is not fully understood.

Purpose of the Study:

• To investigate the role of SVEP1 in monocyte differentiation into macrophages.
• To elucidate the mechanism by which SVEP1 influences monocyte behavior relevant to atherosclerosis.

Main Methods:

• Measured SVEP1 gene expression during monocyte-macrophage differentiation in primary monocytes and THP-1 cells.
• Utilized SVEP1 knockout THP-1 cell lines and an integrin α4β1/α9β1 inhibitor (BOP).
• Assessed cell adhesion, migration, and spreading; quantified downstream integrin signaling via western blotting.

Main Results:

• SVEP1 gene expression increased during monocyte-macrophage differentiation.
• SVEP1 knockout cells showed reduced monocyte adhesion, migration, and spreading.
• Integrin α4β1/α9β1 inhibition yielded similar results, with reduced Rho and Rac1 activity observed in SVEP1 knockout cells.

Conclusions:

• SVEP1 regulates monocyte recruitment and differentiation phenotypes.
• This regulation occurs through an integrin α4β1/α9β1 dependent mechanism.
• SVEP1 plays a novel role in monocyte behavior pertinent to CAD pathophysiology.