Pericytopathy: Oxidative Stress and Impaired Cellular Longevity in the Pancreas and Skeletal Muscle in Metabolic Syndrome and Type 2 Diabetes

Abstract

The pericyte's role has been extensively studied in retinal tissues of diabetic retinopathy; however, little is known regarding its role in such tissues as the pancreas and skeletal muscle. This supportive microvascular mural cell plays an important and novel role in cellular and extracellular matrix remodeling in the pancreas and skeletal muscle of young rodent models representing the metabolic syndrome and type 2 diabetes mellitus (T2DM). Transmission electron microscopy can be used to evaluate these tissues from young rodent models of insulin resistance and T2DM, including the transgenic Ren2 rat, db/db obese insulin resistantߞT2DM mouse, and human islet amyloid polypeptide (HIP) rat model of T2DM. With this method, the earliest pancreatic remodeling change was widening of the islet exocrine interface and pericyte hypercellularity, followed by pericyte differentiation into islet and pancreatic stellate cells with early fibrosis involving the islet exocrine interface and interlobular interstitium. In skeletal muscle there was a unique endothelial capillary connectivity via elongated longitudinal pericyte processes in addition to pericyte to pericyte and pericyte to myocyte cellcell connections allowing for paracrine communication. Initial pericyte activation due to moderate oxidative stress signaling may be followed by hyperplasia, migration and differentiation into adult mesenchymal cells. Continued robust oxidative stress may induce pericyte apoptosis and impaired cellular longevity. Circulating antipericyte autoantibodies have recently been characterized, and may provide a screening method to detect those patients who are developing pericyte loss and are at greater risk for the development of complications of T2DM due to pericytopathy and rarefaction. Once detected, these patients may be offered more aggressive treatment strategies such as early pharmacotherapy in addition to lifestyle changes targeted to maintaining pericyte integrity. In conclusion, we have provided a review of current knowledge regarding the pericyte and novel ultrastructural findings regarding its role in metabolic syndrome and T2DM.