Circulating Endothelial Microparticles Are Associated with Vascular Dysfunction in Patients with End-Stage Renal Failure

Abstract

Endothelial dysfunction and arterial stiffness are major determinants of cardiovascular risk in patients with end-stage renal failure (ESRF). Microparticles are membrane fragments shed from damaged or activated cells. Because microparticles can affect endothelial cells, this study investigated the relationship between circulating microparticles and arterial dysfunction in patients with ESRF and identified the cellular origin of microparticles associated with these alterations. Flow cytometry analysis of platelet-free plasma from 44 patients with ESRF indicated that circulating levels of Annexin V؉ microparticles were increased compared with 32 healthy subjects, as were levels of microparticles derived from endothelial cells (three-fold), platelets (16.5-fold), and erythrocytes (1.6-fold). However, when arterial function was evaluated noninvasively in patients with ESRF, only endothelial microparticle levels correlated highly with loss of flow-mediated dilation (r ‫؍‬ ؊0.543; P ‫؍‬ 0.004), increased aortic pulse wave velocity (r ‫؍‬ 0.642, P < 0.0001), and increased common carotid artery augmentation index (r ‫؍‬ 0.463, P ‫؍‬ 0.0017), whereas platelet-derived, erythrocyte-derived, and Annexin V؉ microparticle levels did not. In vitro, microparticles from patients with ESRF impaired endothelium-dependent relaxations and cyclic guanosine monophosphate generation, whereas microparticles from healthy subjects did not. Moreover, in vitro endothelial dysfunction correlated with endothelial-derived (r ‫؍‬ 0.891; P ‫؍‬ 0.003) but not platelet-derived microparticle concentrations. In fact, endothelial microparticles alone decreased endothelial nitric oxide release by 59 ؎ 7% (P ‫؍‬ 0.025). This study suggests that circulating microparticles of endothelial origin are tightly associated with endothelial dysfunction and arterial dysfunction in ESRF.J (3,4), a systemic disorder and a key variable in the pathogenesis of atherosclerosis and its complications (5). Moreover, arterial wall stiffening, which is partly influenced by nitric oxide (NO) and the endothelium (6,7), occurs frequently during ESRF and has been reported as an independent predictor of cardiovascular events (7-9) Circulating microparticles (MP) are shed membrane vesicles resulting from apoptosis or activation of several cell types in response to various stimuli (10,11). We previously demonstrated that circulating MP that are isolated from patients with acute coronary syndromes directly induce endothelial dysfunction in vitro and hypothesized that this effect could be of clinical relevance (12). In this study, we sought to extend those earlier observations by investigating the possible relationships between circulating MP levels and in vivo arterial properties in patients with ESRF. In addition, we undertook to determine the cellular origin of the circulating MP associated with these vascular alterations. Materials and MethodsWe included 44 patients with ESRF from the Fleury-Mérogis hemodialysis center. Patients were eligible for inclusion when (1) they had ha...

Circulating Microparticles

“…31 We observed recently that very few circulating platelet-derived CD41ϩMPs bind annexin V in some patients with end-stage renal failure, whereas most CD41ϩ MPs from other patients with the same disease were positive for annexin V ( Figure 3). 32 Taken all together, these observations suggest that if phosphatidylserine is exposed on the outer leaflet of these annexin V negative MPs, it may be unavailable for annexin V binding as already engaged in some other molecular interactions. Indeed, phosphatidylserine binds with high affinity to lactadherin, a milk-fat globule glycoprotein found on plasma exosomes, or to proteins from the coagulation cascade, such as protein S, an antithrombotic protein cofactor to protein C. 33,34 These proteinprotein interactions are involved in the phagocytosis of apoptotic cells by macrophages.…”

Microparticles as Biomarkers of Vascular Dysfunction in Metabolic Syndrome and its Individual Components

“…Indeed, several other studies indicate that fewer than 50% of microparticles actually expose phosphatidylserine (Annexin V + ) [14,44]. The authors did not search other microparticle subpopulations which can be altered in pre-hypertension state.…”

Role of extracellular membrane vesicles in the pathogenesis of various diseases, including cancer, renal diseases, atherosclerosis, and arthritis

“…It is possible that they are involved in promoting accelerated arterial calcification and sclerosis, as seen, not only in the affected kidneys but also at multiple sites in arteries throughout the body. 80,81 In CRD, cell-damaging agents such as uremic toxins, low shear stress, and increased arterial stiffness contribute to endothelial apoptosis with a substantial release of endothelial MPs (EMPs) ie, MVs. 81 Under normal physiological conditions, EMP release is local and quite low in the peripheral circulation 82 in contrast to pathological conditions such as endothelial dysfunction in end-stage renal disease 29 and pulmonary arterial hypertension (PAH) 27 in which EMPs are found in high numbers.…”

“…80,81 In CRD, cell-damaging agents such as uremic toxins, low shear stress, and increased arterial stiffness contribute to endothelial apoptosis with a substantial release of endothelial MPs (EMPs) ie, MVs. 81 Under normal physiological conditions, EMP release is local and quite low in the peripheral circulation 82 in contrast to pathological conditions such as endothelial dysfunction in end-stage renal disease 29 and pulmonary arterial hypertension (PAH) 27 in which EMPs are found in high numbers. 27,29 Recent studies have shown that an increased number of plasma membrane-derived microvesicles (200-1000 nm in diameter) in the pulmonary circulation (referred to as 'MPs') represent an excellent biomarker for determining the severity of PAH.…”

“…113 An important refinement in the current laboratory tests is the ability to identify circulating endothelial-derived MPs, and measure their occurrence in diseased patients. Amabile et al 29,81,114 demonstrated the potential of circulating MVs as diagnostic markers to assess cardiovascular events in hypertension and in renal disease by evaluating the number of circulating endothelial MPs. Beyer and Pisetsky 115 summarized the state of the art diagnostic techniques in defining the role of MPs as biomarkers for vasculitides, PAH, and systemic sclerosis.…”