Extracellular vesicles in diabetes mellitus induce alterations in endothelial cell morphology and migration

Sharon F Wu,Nicole Noren Hooten,Nicolle A Mode,Michele K Evans,Alan B Zonderman,David W Freeman

doi:10.1186/s12967-020-02398-6

Abstract

BackgroundInflammation-related atherosclerotic peripheral vascular disease is a major end organ complication of diabetes mellitus that results in devastating morbidity and mortality. Extracellular vesicles (EVs) are nano-sized particles that contain molecular cargo and circulate in the blood. Here, we examined EV protein cargo from diabetic individuals and whether these EVs cause functional changes in endothelial cells.MethodsWe quantified inflammatory protein levels in plasma-derived EVs from a longitudinal cohort of euglycemic and diabetic individuals and used in vitro endothelial cell biological assays to assess the functional effects of these EVs with samples from a cross-sectional cohort.ResultsWe found several significant associations between EV inflammatory protein levels and diabetes status. The angiogenic factor, vascular endothelial growth factor A (VEGF-A), was associated with diabetes status in our longitudinal cohort. Those with diabetes mellitus had higher EV VEGF-A levels compared to euglycemic individuals. Additionally, EV levels of VEGF-A were significantly associated with homeostatic model assessment of insulin resistance (HOMA-IR) and β-cell function (HOMA-B). To test whether EVs with different inflammatory cargo can demonstrate different effects on endothelial cells, we performed cell migration and immunofluorescence assays. We observed that EVs from diabetic individuals increased cell lamellipodia formation and migration when compared to EVs from euglycemic individuals.ConclusionsHigher levels of inflammatory proteins were found in EVs from diabetic individuals. Our data implicate EVs as playing important roles in peripheral vascular disease that occur in individuals with diabetes mellitus and suggest that EVs may serve as an informative diagnostic tool for the disease.

Highlights

Inflammation-related atherosclerotic peripheral vascular disease is a major end organ complication of diabetes mellitus that results in devastating morbidity and mortality
Association of Extracellular vesicle (EV) protein levels with diabetes status Previous data suggested that EVs from diabetic individuals may contribute to heightened inflammation [27]
EVs from individuals with diabetes increase cell migration Given the association that we found between EV inflammatory protein content and diabetes status, we examined whether EVs from diabetic individuals affected cell behavior in vitro

Summary

Introduction

Inflammation-related atherosclerotic peripheral vascular disease is a major end organ complication of diabetes mellitus that results in devastating morbidity and mortality. We examined EV protein cargo from diabetic individuals and whether these EVs cause functional changes in endothelial cells. Type 2 diabetes is a complex, age-associated metabolic disorder characterized by low-grade chronic inflammation [2], hyperinsulinemia [3], insulin resistance, and β-cell dysfunction. It increases the risk for numerous vascular-related comorbidities, including end-stage renal. In addition to the aged population, diabetes causes disproportionate morbidity and mortality among minority groups in the U.S, including African Americans, Hispanics, and Native Americans [1]. In order to create diagnostic tools and therapies that will benefit a broad spectrum of the population, more knowledge of the mechanisms that drive vascular disease in diabetes is needed

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