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Updated: Sep 15, 2025
On-Chip Endothelial Inflammatory Phenotyping
Published on: July 21, 2012
Shear-Induced Macrophage Secretome Promotes Endothelial Permeability
Insights
Pathological shear stress causes macrophages to increase inflammation and endothelial permeability, contributing to discrete subaortic stenosis (DSS) recurrence. Targeting this macrophage-endothelial cell crosstalk may offer new therapeutic strategies for DSS.
Area of Science:
- Cardiovascular Biology
- Immunology
- Pathophysiology
Background:
- Discrete subaortic stenosis (DSS) is a pediatric cardiovascular disease characterized by fibrotic growth in the left ventricular outflow tract (LVOT).
- High recurrence rates post-surgery suggest complex underlying mechanisms involving hemodynamic shear stress.
- The impact of shear stress on macrophage-endothelial cell interactions in DSS remains poorly understood.
Purpose of the Study:
- To investigate the effects of pathological shear stress on human macrophages and their interactions with endothelial cells.
- To elucidate the role of macrophage-endothelial cell crosstalk in the inflammatory processes relevant to DSS.
Main Methods:
- Human monocyte-derived macrophages (MDMs) and human aortic endothelial cells (HAECs) were exposed to shear stress.
- Cellular responses were assessed via gene expression, permeability assays, chemotaxis, and ELISAs.
- Macrophage-endothelial cell crosstalk was evaluated using conditioned media transfers.
Main Results:
- Shear stress induced a pro-inflammatory response in MDMs, upregulating TNF and CXCL8.
- MDM-conditioned media increased HAEC permeability and inflammatory marker expression (VCAM-1, ICAM-1).
- Macrophage-secreted factors promoted monocyte migration and altered endothelial cell junction proteins (VE-Cadherin, CD31).
Conclusions:
- Pathological shear stress drives macrophages to release factors that increase endothelial permeability and inflammation.
- This inflammatory crosstalk likely contributes to fibrosis and recurrence in DSS.
- Targeting macrophage-endothelial cell interactions presents a potential therapeutic strategy to mitigate DSS fibrosis and improve outcomes.
Background:
Discrete subaortic stenosis is a pediatric cardiovascular disease marked by fibrotic growth within the left ventricular outflow tract (LVOT), leading to severe complications, including left ventricular hypertrophy, aortic regurgitation, and arrhythmias. Despite surgical intervention, a 20-30% recurrence rate suggests a complex underlying pathophysiology. Elevated flow and resultant hemodynamic shear stress within the LVOT are key factors in DSS development. While effects of shear stress on endothelial cells have been studied, the impact on macrophages and their interactions with endothelial cells remains unclear.
Methods:
In this study, human monocyte-derived macrophages (MDMs) and human aortic endothelial cells (HAECs) were subjected to shear stress using a cone-and-plate viscometer. Cellular crosstalk was evaluated through conditioned media (CM) transfers. Gene expression, permeability and chemotaxis assays, immunofluorescent staining, and ELISAs assessed cellular responses.
Results:
MDMs exposed to shear stress exhibited a pro-inflammatory response with upregulated TNF and CXCL8 genes. HAECs exposed to MDM-CM showed increased expression of inflammatory markers (VCAM-1, ICAM-1) and decreased VE-Cadherin and CD31, indicating increased permeability. Permeability assays confirmed that HAECs became more permeable when exposed to MDM-CM. Chemotaxis assays showed time-dependent monocyte migration in both MDM-CM and HAEC-CM. Immunofluorescent staining revealed diminished VE-Cadherin and CD31 in HAECs exposed to MDM-CM.
Conclusions:
Overall, pathological shear stress induced macrophages to secrete factors that increased endothelial permeability and perpetuated an inflammatory response. This interaction likely exacerbates fibrosis in DSS, promoting recurrence post-surgery. Understanding these mechanisms opens potential therapeutic avenues targeting inflammatory crosstalk between macrophages and endothelial cells, which could mitigate fibrosis and improve patient outcomes.
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