Serum exosomes mediate delivery of arginase 1 as a novel mechanism for endothelial dysfunction in diabetes

Abstract

Exosomes, abundant in blood, deliver various molecules to recipient cells. Endothelial cells are directly exposed to circulating substances. However, how endothelial cells respond to serum exosomes (SExos) and the implications in diabetes-associated vasculopathy have never been explored. In the present study, we showed that SExos from diabetic <i>db</i><i>/db</i> mice (<i>db/db</i> SExos) were taken up by aortic endothelial cells, which severely impaired endothelial function in nondiabetic <i>db/m</i>^<i>+</i> mice. The exosomal proteins, rather than RNAs, mostly account for <i>db/db</i> SExos-induced endothelial dysfunction. Comparative proteomics analysis showed significant increase of arginase 1 in <i>db/db</i> SExos. Silence or overexpression of arginase 1 confirmed its essential role in <i>db/db</i> SExos-induced endothelial dysfunction. This study is a demonstration that SExos deliver arginase 1 protein to endothelial cells, representing a cellular mechanism during development of diabetic endothelial dysfunction. The results expand the scope of blood-borne substances that monitor vascular homeostasis.