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P-selectin and MAC-1 mediate monocyte rolling and adhesion to ECM-bound platelets under flow conditions
P H Kuijper1, H I Gallardo Torres, L A Houben
1Department of Pulmonary Diseases, University Hospital Utrecht, The Netherlands. P.Kuijper@hli.azu.nl
Abstract:
Accumulation of monocyte-derived foam cells in focal areas of the atherosclerotic (A.S.-) lesion is one of the key events in early atherogenesis. Using a flow model for the damaged vessel wall, we examined the ability of ECM-bound platelets to induce monocyte tethering and adhesion. Whereas ECM-proteins alone induced monocyte adhesion only at low shear stresses (< 100 mPa), ECM-bound platelets induced monocyte rolling and adhesion at shear stresses up to 240 mPa. Studies with specific antibodies showed that monocyte adhesion to platelets was mainly mediated by P-selectin and monocyte PSGL-1 (maximum inhibition 90%). beta2-Integrin blocking CD18 and CD11b antibodies partly inhibited the arrest of rolling cells. Antibodies against other adhesion molecules such as LFA-1, PECAM-1, and beta1-integrins had no effect. Even sparsely adhered platelets (approximately 10% coverage of the surface) already strongly supported monocyte tethering. In conclusion, activated platelets present on ECM are a powerful adhesive substrate for monocyte recruitment under flow conditions.
Insights
Platelets bound to the extracellular matrix (ECM) powerfully recruit monocytes to damaged vessel walls, initiating early atherosclerosis. This platelet-mediated monocyte adhesion occurs even at high shear stress.
Area of Science:
- Cardiovascular Biology
- Atherosclerosis Research
- Hemostasis and Thrombosis
Background:
- Monocyte-derived foam cells are key in early atherosclerotic lesion development.
- Understanding monocyte recruitment to damaged vessel walls is crucial for atherogenesis research.
Purpose of the Study:
- To investigate the role of extracellular matrix (ECM)-bound platelets in inducing monocyte tethering and adhesion under flow conditions.
- To elucidate the molecular mechanisms mediating monocyte adhesion to ECM-bound platelets.
Main Methods:
- Utilized a flow model simulating a damaged vessel wall.
- Examined monocyte adhesion to ECM proteins versus ECM-bound platelets at varying shear stresses.
- Employed specific antibodies to block key adhesion molecules (P-selectin, PSGL-1, beta2-Integrin, LFA-1, PECAM-1, beta1-integrins).
Main Results:
- ECM-bound platelets significantly enhanced monocyte rolling and adhesion compared to ECM proteins alone, up to 240 mPa shear stress.
- Monocyte adhesion to platelets was primarily mediated by P-selectin on platelets and PSGL-1 on monocytes (90% inhibition).
- Beta2-Integrin (CD18/CD11b) partially inhibited the arrest of rolling monocytes; other tested adhesion molecules had no significant effect.
- Even low surface coverage of platelets (10%) strongly supported monocyte tethering.
Conclusions:
- Activated platelets on the ECM serve as a potent substrate for monocyte recruitment under flow.
- The P-selectin/PSGL-1 axis is critical for platelet-mediated monocyte adhesion in this context.
- These findings highlight a significant mechanism in early atherogenesis and inflammatory responses within the vasculature.