Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes
Luciana Mateus Gonçalves,
Mirza Muhammad Fahd Qadir,
Maria Boulina,
Madina Makhmutova,
Elizabeth Pereira,
Joana Almaça
Affiliations
Luciana Mateus Gonçalves
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
Mirza Muhammad Fahd Qadir
Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA; Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA, USA
Maria Boulina
Diabetes Research Institute, University of Miami, Miami, FL, USA
Madina Makhmutova
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
Elizabeth Pereira
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA
Joana Almaça
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA; Molecular and Cellular Pharmacology Graduate Program, University of Miami Miller School of Medicine, Miami, FL, USA; Corresponding author
Summary: Pancreatic islets are endocrine organs that depend on their microvasculature to function. 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 investigate islet pericyte density, phenotype, and function using living pancreas slices from donors without diabetes, donors with a single T1D-associated autoantibody (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 toward myofibroblasts. Using publicly available RNA sequencing (RNA-seq) data, we further found that transcriptional alterations related to endothelin-1 signaling and vascular and extracellular matrix (ECM) remodeling are hallmarks of single autoantibody (Aab)+ donor pancreata. Our data show that microvascular dysfunction is present at early stages of islet autoimmunity.
