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.HighlightsChanges in islet pericyte coverage and phenotype occur during T1D progression.Vascular responses to vasoactive stimuli are impaired in islets from Aab+ and T1D donors.Endothelin-1 action and receptor expression are altered in vascular cells from Aab+ and T1D donors.Strong vascular remodeling occurs in the pancreas of Aab+ and T1D donors.

Diabetes as a Pancreatic Microvascular Disease—A Pericytic Perspective

“…9 In T1D, we also a found a decrease in the pericyte-to-endothelial cell ratio, and several capillaries in T1D islets lacked pericytes or were covered by pericytes with an abnormal morphology. 37 These data suggest that, under diabetic conditions, islets may lose a source of trophic factors that maintain beta cell mature phenotype and function, as well as the capacity to control their own blood flow. These changes can lead to inadequate plasma insulin levels, further deteriorating glycemic control.…”

“…38 Using publicly available single-cell ribonucleic acid (RNA) sequencing data from human islets (from the Human Pancreas Analysis Program), 39 we recently found that the levels of several genes involved in tissue response to hypoxia, vascular remodeling and endothelin-1 signaling were significantly altered in islet cells from single Aab+ organ donors (GADA+). 37 In summary, significant remodeling and adaptations at the level of the islet microvasculature occur in T1D pancreata at early stages.…”

“…9,13,85 By contrast, activating beta cells by increasing extracellular glucose concentration decreases [Ca 2+ ]i in pericytes, dilating islet capillaries, and increasing local blood flow. 9,37 We concluded that pericytes control islet capillary diameter and blood flow under different metabolic states: upon activation of beta cells with high glucose, pericytes relax and blood vessels dilate, allowing an increase in blood flow in the islet; upon activation of the sympathetic nervous system, pericyte [Ca 2+ ]i levels increase and blood vessels constrict, leading to a decrease in local blood flow. 9…”

“…19 Another imaging study using mass cytometry reported that islet vascular density was significantly reduced only in the head of the pancreas in T1D donors, irrespective of the duration of T1D (from 0 to 21 years), but it was reduced in all regions of the pancreas in individuals that had recently been diagnosed (T1D for less than 2 years). 23 Other studies examining pancreata from T1D organ donors have shown that capillaries persist in islets despite loss of beta cells, [36][37][38] indicating that changes in islet vessel density may be more variable in humans, depend on the region of the pancreas examined, as well as on the duration of the disease. Nonetheless, it would be interesting to know if these blood vessels that are still present in T1D pancreata remain functional or whether they just reflect active vascular remodeling or angiogenesis taking place.…”

“…2 and 3). 37 Studies have shown that several components of the islet ECM are significantly altered in diabetes, including laminins, collagens, heparan sulfate/heparan sulfate proteoglycans, and hyaluronan, as well as the enzymes that degrade these molecules. 40 Some islets from T1D organ donors with short disease duration may even contain amyloid deposits.…”