Increased circulating microparticles in streptozotocin‐induced diabetes propagate inflammation contributing to microvascular dysfunction

Abstract

In various cardiovascular diseases, microparticles (MPs), the membrane‐derived vesicles released during cell activation, are markedly increased in the circulation. These MPs have been recognized to play diverse roles in the regulation of cellular functions. However, current knowledge of MP function has been largely concluded from in vitro studies. The precise impact of disease‐induced MPs on vascular inflammation and disease progression remain obscure. In this study we investigated the biogenesis, profile, and functional roles of circulating MPs using a streptozotocin‐induced diabetic rat model with well‐characterized microvascular functions. Our study revealed an over 130‐fold MP increase in plasma of diabetic rats compared to normal rats. Majority of these MPs originate from platelets, leukocytes, and endothelial cells and circulate as aggregates. Diabetic MPs show greater externalized phosphatidylserine (PS) than normal MPs. When diabetic plasma or isolated diabetic MPs were perfused into normal microvessels or systemically transfused into normal rats, MPs immediately adhered to endothelium and subsequently mediated leukocyte adhesion. These microvessels then exhibited augmented permeability responses to inflammatory mediators, replicating the microvascular manifestations observed in diabetic rats. These effects were abrogated when MPs were removed from diabetic plasma or when diabetic MPs were pre‐coated with a lipid‐binding protein, Annexin‐V, suggesting externalized PS to be key in mediating MP interactions with endothelium and leukocytes. Our study demonstrated that the elevated MPs in diabetic plasma are actively involved in the propagation of vascular inflammation through their adhesive surfaces, providing mechanistic insight into the pathogenesis of multi‐organ‐involved vascular dysfunction that commonly occurred in diabetic patients.

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