Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes

Abstract

Pancreatic islets are endocrine organs that depend on their microvasculature to function properly. Along with endothelial cells, pericytes comprise the islet microvascular network. These mural cells are crucial for microvascular stability and function, but it is not known if/how they are affected during the development of type 1 diabetes (T1D). Here we investigated islet pericyte density, phenotype and function using living pancreas slices from donors without diabetes, donors with a single T1D-associated autoantibody (Aab+; all GADA+) and recent onset T1D cases. Our data show that islet pericyte and capillary responses to vasoactive stimuli are impaired early on in T1D. Microvascular dysfunction is associated with a switch in the phenotype of islet pericytes towards pro-fibrotic myofibroblasts. Using publicly available RNAseq data, we further found that transcriptional alterations related to endothelin-1 signaling, vascular and ECM remodeling are hallmarks of single Aab+ donor pancreata. Our data show that islet pericyte/microvascular dysfunction is present at early stages of islet autoimmunity. HighlightsO_LIChanges in islet pericyte coverage and phenotype occur during T1D progression. C_LIO_LIVascular responses to vasoactive stimuli are impaired in islets from Aab+ and T1D donors. C_LIO_LIEndothelin-1 action and receptor expression are altered in vascular cells from Aab+ and T1D donors. C_LIO_LIStrong vascular remodeling occurs in the pancreas of Aab+ and T1D donors. C_LI