A Multiscale Computational Model of Endothelial-Immune Cell Interactions Regulated by Dynamic Wall Shear Stress

Area of Science:

• Cardiovascular Research
• Computational Biology
• Immunology

Background:

• Atherosclerotic plaque formation alters vascular geometry, causing disturbed blood flow and heterogeneous wall shear stress (WSS).
• Spatial WSS heterogeneity is critical in endothelial dysfunction and immune cell recruitment during atherogenesis.
• The dynamic impact of WSS heterogeneity on endothelial-immune interactions is not fully understood.

Purpose of the Study:

• To investigate endothelial cell (EC) phenotype transitions and immune cell dynamics under varying conditions of nitric oxide (NO) damage threshold (D_NO).
• To develop a multiscale computational model integrating hemodynamics, EC phenotype transitions, and immune responses.
• To elucidate the role of WSS heterogeneity in vascular inflammation and lesion development.

Main Methods:

• Developed a multiscale computational model integrating hemodynamics, EC phenotype transitions, and immune responses.
• Simulated EC phenotype transitions and immune cell dynamics under varying D_NO conditions.
• Analyzed the effects of low-shear stress regions and NO depletion on ECs and immune cell recruitment.

Main Results:

• Low-shear stress regions expanded with increasing D_NO, decreasing nitric oxide (NO) production.
• Accelerated EC activation and death were observed due to decreased NO.
• Elevated Monocyte Chemoattractant Protein-1 (MCP-1) expression enhanced monocyte recruitment and M1 macrophage polarization.

Conclusions:

• Dynamic WSS heterogeneity drives EC state transitions and regulates immune cell recruitment and differentiation.
• Spatially heterogeneous WSS induces local NO depletion, explaining focal endothelial dysfunction and promoting inflammatory lesion development.
• The model provides mechanistic insights into the interplay between mechanical forces and vascular immune responses, guiding therapeutic strategies.