Endothelial-derived extracellular vesicles as potential mediators of impaired angiogenesis and cardiovascular disease in pediatric chronic kidney disease

Cardiovascular disease (CVD) is the leading cause of mortality in chronic kidney disease (CKD). However, the pathogenesis of CVD in CKD remains incompletely understood. Extracellular vesicles (EVs) have emerged as mediators of inter-organ cross-talk and endothelial EVs (EC-EVs) have previously been associated with CVD. We hypothesized that CKD alters EV release and cargo and subsequently promotes vascular remodeling. A cohort of 94 children with different stages of CKD, including patients after kidney transplantation and age-matched healthy donors, was recruited, yielding phenotypical and functional EV analyses in the absence of age-related comorbidities. Plasma EC-EV concentrations were found elevated in hemodialysis patients and decreased after receiving kidney transplantation. Sequencing revealed lower abundance of 30 microRNAs in CKD EVs with predicted importance in angiogenesis and smooth muscle cell proliferation. In vitro, CKD EVs induced transcriptomic changes of genes involved in angiogenesis pathways and functionally impaired angiogenic properties, migration and proliferation in endothelial cells. High shear stress, as generated by arterio-venous fistulas, and uremic toxins such as indoxyl sulfate were considered as potential drivers of EV release, but only the combination of both triggers increased EV formation from venous endothelial cells. Resulting EVs recapitulated EV miRNA changes observed in CKD in vivo. In conclusion, CKD results in the release of EVs with altered miRNA profiles and the ability to impair angiogenesis, thus potentially mediating vascular pathology in children with CKD. EVs and their miRNA cargo may represent future therapeutic targets to attenuate CVD in CKD.Here, we provide raw bulk RNA sequencing data from commercially available human aortic endothelial cells (HAOECs) treated with EVs from healthy controls (KG), CKD patients receiving hemodialysis (HD) and kidney transplants recipients (NTX). HAoECs were incubated with patient EVs for 18 hours. The cell culture experiments and sequencing were carried out in two batches, each consisting of an N=3 of patients samples per group, yielding an N=6 per patient group and N=18 total.