The effects of microvesicles on endothelial progenitor cells are compromised in type 2 diabetic patients via downregulation of the miR-126/VEGFR2 pathway

Abstract

Our previous study showed that circulating microvesicles (cMVs) of diabetic mice have negative effects on the function of endothelial progenitor cells (EPCs). Whether this is true in diabetic patients deserves further study. In this study, the effects of cMVs and EPC-derived MVs (EPC-MVs) on EPC migration, apoptosis, and reactive oxygen species (ROS) production in healthy controls, well-controlled, and uncontrolled diabetic patients were investigated. The levels of miR-126 and vascular endothelial growth factor receptor 2 (VEGFR2) in cMVs, EPC-MVs, and/or EPCs were analyzed. Moreover, miR-126 inhibitor or mimic was applied to EPCs to modulate the miR-126 level in EPC-MVs. We found the following: 1) the circulating EPC level was reduced but the circulating EPC-MV level increased in uncontrolled diabetic patients; 2) the cMVs and EPC-MVs of healthy controls had beneficial effects on EPCs (migration, apoptosis, ROS), whereas the effects were reversely changed in the cMVs and EPC-MVs of uncontrolled diabetic patients; and 3) the cMVs and EPC-MVs of uncontrolled diabetic patients carried less miR-126 and had downregulated VEGFR2 expression in EPCs. Manipulating the miR-126 level in EPC-MVs with inhibitor or mimic changed their function. The effects of cMVs and EPC-MVs are compromised in diabetes due to the reduction of their carried miR-126, which might provide a therapy target for diabetic vascular complications.

Loading MiR-210 in Endothelial Progenitor Cells Derived Exosomes Boosts Their Beneficial Effects on Hypoxia/Reoxygeneation-Injured Human Endothelial Cells via Protecting Mitochondrial Function

“…Previous reports by us and others showing that EPC-derived extracellular microvesicles shuttle miR-126 [7][8][9]. The protective effects of EPC-EXs on H/R-injured ECs is probably due to their carried miR-126 which has been shown to have beneficial effects on ECs/EPC survival and angiogenic function [30,36] and have modulatory effects on mitochondrion [37]. However, whether these molecules are responsible for the observed effects of EPC-EXs need further investigation.…”

“…In the present study, we proposed to explore whether overexpressing miR-210 in EPC-EXs would enhance the protective of EPC-EXs. The rationale is based on followings: a) EPC transfusion has therapeutic effects on ischemic stroke [39]; b) The potential mechanisms of stem cell therapy for ischemic stroke have been partially attributed to their released microvesicels or EXs [10,11]; c) EPC-released microvesicels have shown angiogenic function in ECs/EPCs by delivering their carried miR-126 [30]; d) miR-210 has shown therapeutic potential for ischemic disease [18]. To determine the role of miR-210 in EPC-EXs, we successfully produced miR-210 enriched EPC-EXs by transfecting EPCs with miR-210 mimics.…”

“…The migration ability of ECs was determined by scratch assay [30]. In brief, ECs were grown to confluence on 6-well cell culture plates.…”

Diabetic microangiopathy: Pathogenetic insights and novel therapeutic approaches

“…EPCs have a therapeutic impact on cardiovascular tissue repair and regeneration by playing various roles in the formation of new blood vessels, including mobilization, migration, adhesion, differentiation of vascular cells, and the production of adequate circulating levels of growth factors and chemokines, necessary for tissue repair and regeneration [27][28][29][30]. In fact, experimental and clinical studies suggest that EPCs can home to sites of a pre-existing vessel, and from there form neovessels under the influence of VEGF, chemokines and integrins, including monocyte chemoattractant protein (MCP)-1, stromal cell derived factor-1 (SDF-1), angiopoietin (Ang-1) and the α4β1 integrin [31][32][33][34][35]. Dysregulated levels of these molecules may contribute to a decrease in the number and function of EPCs in diabetes [31][32][33][34]36].…”

“…In fact, experimental and clinical studies suggest that EPCs can home to sites of a pre-existing vessel, and from there form neovessels under the influence of VEGF, chemokines and integrins, including monocyte chemoattractant protein (MCP)-1, stromal cell derived factor-1 (SDF-1), angiopoietin (Ang-1) and the α4β1 integrin [31][32][33][34][35]. Dysregulated levels of these molecules may contribute to a decrease in the number and function of EPCs in diabetes [31][32][33][34]36]. These defects are associated with a more rapid progression of microvascular disease [37].…”