Abstract

Endothelial cell-derived extracellular vesicles (CD31EVs) are a new entity for therapeutic/prognostic purposes. The roles of CD31EVs as mediators of smooth muscle cell (VSMC) dysfunction in type 2 diabetes (T2D) is investigated herein.

We demonstrated that, unlike non-diabetic, diabetic serum-derived-EVs (D-CD31EVs) boosted apoptosis resistance of VSMCs cultured in hyperglycaemic condition. Biochemical analysis revealed that this effect relies on changes in the balance between anti-apoptotic/pro-apoptotic signals: increase of bcl-2 and decrease of bak/bax. D-CD31EV cargo analysis demonstrated that D-CD31EVs are enriched in membrane-bound-platelet-derived-growth-factor-BB (mbPDGF-BB). Thus, we postulated that mbPDGF-BB transfer by D-CD31EVs could account for VSMC resistance to apoptosis. By depleting CD31EVs of PDGF-BB or blocking the PDGF-BB-receptorβ on VSMCs, we demonstrated that mbPDGF-BB contributes to D-CD31EV-mediated bak/bax and bcl-2 levels. Moreover, we found that bak expression is under the control of PDGF-BB-mediated miR-296-5p expression. In fact, while PDGF-BB-treatment recapitulated D-CD31EV-mediated anti-apoptotic program and VSMC resistance to apoptosis, PDGF-BB-depleted CD31EVs failed. D-CD31EVs also increased VSMC migration and recruitment to neovessels, by means of PDGF-BB. Finally, we found that VSMCs, from human atherosclerotic arteries of T2D individuals, express low bak/bax and high bcl-2 and miR-296-5p levels.

This study identifies the mbPDGF-BB in D-CD31EVs as a relevant mediator of diabetes-associated VSMC resistance to apoptosis.