Microparticles From Human Atherosclerotic Plaques Promote Endothelial ICAM-1–Dependent Monocyte Adhesion and Transendothelial Migration

Abstract

Rationale and Objective: Membrane-shed submicron microparticles (MPs) released following cell activation or apoptosis accumulate in atherosclerotic plaques, where they stimulate endothelial proliferation and neovessel formation. The aim of the study was to assess whether or not MPs isolated from human atherosclerotic plaques contribute to increased endothelial adhesion molecules expression and monocyte recruitment. Method and Results:Human umbilical vein and coronary artery endothelial cells were exposed to MPs isolated from endarterectomy specimens (n‫)26؍‬ and characterized by externalized phosphatidylserine. Endothelial exposure to plaque, but not circulating, MPs increased ICAM-1 levels in a concentration-dependant manner (3.4-fold increase) without affecting ICAM-1 mRNA levels. Plaque MPs harbored ICAM-1 and transferred this adhesion molecule to endothelial cell membrane in a phosphatidylserine-dependent manner. MP-borne ICAM-1 was functionally integrated into cell membrane as demonstrated by the increased ERK1/2 phosphorylation following ICAM-1 ligation. Plaque MPs stimulated endothelial monocyte adhesion both in culture and in isolated perfused mouse carotid. This effect was also observed under flow condition and was prevented by anti-LFA-1 and anti-ICAM-1 neutralizing antibodies. MPs isolated from symptomatic plaques were more potent in stimulating monocyte adhesion than MPs from asymptomatic patients. Plaque MPs did not affect the release of interleukin-6, interleukin-8, or MCP-1, nor the expression of VCAM-1 and E-selectin. Key Words: microparticle Ⅲ ICAM-1 Ⅲ adhesion Ⅲ monocyte Ⅲ microvesicle A therosclerosis is a chronic inflammatory disease characterized by the accumulation of leukocytes, lipids, and fibrous tissue in the intima of arteries. 1 In atherosclerotic plaques, endothelial cells express elevated amounts of adhesion molecules such as selectins (P-selectin and E-selectin) and intercellular (ICAM-1) and vascular (VCAM-1) adhesion molecules at their surface. 1,2 Cytokines and chemokines are also secreted in excess by activated vascular cells in this context. These conditions favor the recruitment and the accumulation of monocytes and lymphocytes in the intima of vessels. 1,2 Human atherosclerotic plaques contain large amounts of microparticles (MPs), which are submicron membrane vesicles released following cell activation or apoptosis. [3][4][5] MPs harbor at their surface most of the membrane-associated proteins of the cells they stem from and are characterized by the loss of plasma membrane asymmetry resulting in the exposure of phosphatidylserine on their outer leaflet. 6,7 MPs isolated from human atherosclerotic lesions are highly thrombogenic and originate from multiple cells, including macrophages, lymphocytes, erythrocytes, and smooth muscle and endothelial cells. 4,5 MPs are no longer taken as innocent bystanders because several studies point out that MPs generated in vitro from cultured cells can affect several cellular functions, including inflammatory responses. 8 -15 However,...

Thrombus Aspiration Therapy and Coronary Thrombus Components in Patients with Acute ST-Elevation Myocardial Infarction

“…Microparticles (MPs) are 0.1-1-μm membrane vesicles that are released into the extracellular space following cell activation or apoptosis 33) . Several cardiovascular risk factors, such as oxidative stress and elevated levels of lipoproteins and cytokines, increase the release of MPs from vascular/circulation cells 34,35) , and a large number of studies have proposed that MPs may contribute to atherosclerotic plaque development and thrombus formation/progression [35][36][37][38] . In fact, circulating MPs (primarily endothelial and leukocyte MPs), which contribute to the initiation of atherosclerosis due to endothelial dysfunction by decreasing nitric oxide synthesis, have been reported to be significantly higher in ACS patients 39) and are considered to be a primary source of the blood-borne tissue factor involved in thrombus propagation at the site of vascular injury 38,40,41) .…”

“…At the time of plaque disruption, locally released tissue factor-positive and leukocyte-derived MPs play an important role in fibrin-rich thrombus formation [35][36][37][38][39][40][41][42] . Moreover, activated inflammatory cells, such as neutrophils, macrophages and eosinophils, contribute to the growth of a thrombus 17,89,90) .…”

Circulating Microparticles Decrease After Cardiac Stress in Patients With Significant Coronary Artery Stenosis

“…18 Circulating annexin V is a ligand for PS and inhibits the uptake of MPs into endothelial cells. 21 The level of circulating annexin V was not different before and after cardiac stress in patients with or without significant coronary stenosis ( Figure 3B), suggesting an annexin V-independent regulation of EMP uptake. In contrast, stimulation of target endothelial cells with sera collected from patients with coronary stenosis after cardiac stress augmented expression of endothelial PSR, a main regulator of EMP uptake ( Figure 3C).…”

Erratum: Inflammatory processes in cardiovascular disease: a route to targeted therapies

“…Early findings utilizing this approach seem to corroborate observations from genome-wide association studies as well as plaque compositional changes in plaque revealed by highresolution MRI Chai, personal communication. Circulating multivesicular bodies derived from platelets, monocytes, and red blood cells have also been characterized specifically with regard to the miRNA that they contain, and have been shown to have roles in VCAM1 inhibition, activation of plaque macrophages, and in cell-to-cell signalling 147 that are central to atherosclerosis progression 148 .…”