No abstract

The chemokines platelet factor 4 (PF4) and RANTES (regulated on activation normal T cell expressed and secreted) are secreted by activated platelets and influence multiple cell types and biologic processes. For instance, PF4 inhibits progenitor cell proliferation and angiogenesis, while platelet-derived RANTES is involved in vascular recruitment of monocytes.

Background-Angiogenic early outgrowth cells (EOCs) have been reported to contribute to endothelial regeneration and to limit neointima formation after vascular injury. Vascular pathologies comprise platelet activation and concomitant generation of platelet microparticles (PMPs). We hypothesized that PMPs may interact with EOCs in the context of vascular injury and modulate their regenerative potential. Methods and Results-Using flow cytometry, confocal microscopy, and scanning electron microscopy, we demonstrated the binding of thrombin/collagen-induced PMPs to EOCs with subsequent membrane assimilation and incorporation. This interaction promoted phenotypic alterations of EOCs with increased expression of endothelial cell markers and transfer of the chemokine receptor CXCR4 to EOCs with enhanced responsiveness to its ligand CXCL12/SDF-1␣. In addition, PMPs augmented the adhesion of EOCs to extracellular matrix components and to the injured vessel wall and accelerated cytoskeletal reorganization and migration of EOCs. PMPs induced changes in the EOC secretome toward a more proangiogenic profile and amplified the EOC-mediated induction of proliferation, migration, and capillary tube formation by mature endothelial cells. Compared with untreated EOCs, the injection of PMP-treated EOCs resulted in accelerated reendothelialization after arterial denudation injury in athymic nude mice, whereas the EOC-mediated reduction of neointima formation remained unchanged. Conclusions-Our data provide evidence that PMPs can boost the potential of EOCs to restore endothelial integrity after vascular injury. Major mechanisms involve the enhancement of EOC recruitment, migration, differentiation, and release of proangiogenic factors. (Circulation. 2010;122:495-506.)Key Words: endothelium Ⅲ inflammation Ⅲ restenosis Ⅲ platelets R estenosis resulting from neointimal hyperplasia, negative remodeling, and elastic recoil is considered the Achilles heel of interventional cardiology. 1 In addition to the control of inflammatory reactions and smooth muscle cell (SMC) expansion, reendothelialization after vascular damage is a crucial mechanism limiting neointima formation. 2 Endothelial regeneration at sites of primary or iatrogenic vascular injury has been thought to rely mainly on the migration and proliferation of resident endothelial cells from the adjacent intact vasculature. However, recent studies revised this concept by demonstrating that angiogenic early outgrowth cells (EOCs), which exhibit phenotypic features of myeloid and endothelial cells and are known as endothelial progenitor cells, are recruited to sites of injury and accelerate reendothelialization. 3 Notably, infusion of EOCs attenuates neointimal hyperplasia after arterial injury. 4 -6 Furthermore, EOCs may contribute to neovascularization in both ischemic hind limbs and acute myocardial infarction models. 7 Clinical studies demonstrating a negative correlation of the number and functional capacity of circulating CD34 ϩ vascular endothelial growth factor receptor-2 (V...

Objective-Platelet activation mediates multiple cellular responses, including secretion of chemokines such as RANTES (CCL5), and formation of platelet microparticles (PMPs). We studied the role of PMPs in delivering RANTES and promoting monocyte recruitment. Methods and Results-Here we show that PMPs contain substantial amounts of RANTES and deposit RANTES on activated endothelium or murine atherosclerotic carotid arteries. RANTES deposition is facilitated by flow conditions and more efficient than that conferred by PMP supernatants. Interactions of PMPs with activated endothelium in flow were mostly characterized by rolling. RANTES deposition showed a diffuse distribution pattern and was rarely colocalized with firmly adherent PMPs, substantiating that RANTES deposition occurs during transient interactions. Importantly, preperfusion with PMPs enhanced monocyte arrest on activated endothelium or atherosclerotic carotid arteries, which could be inhibited by a blocking antibody or a RANTES receptor antagonist. Blockade or deficiency of PMP-expressed adhesion receptors demonstrated differential requirement of P-selectin, glycoprotein Ib (GPIb), GPIIb/IIIa, and junctional adhesion molecule-A for PMP interactions with endothelium, PMP-dependent RANTES deposition, and subsequent monocyte arrest. Conclusion-Circulating PMPs may serve as a finely tuned transcellular delivery system for RANTES, triggering monocyte arrest to inflamed and atherosclerotic endothelium, introducing a novel mechanism for platelet-dependent monocyte recruitment in inflammation and atherosclerosis.