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01-08-2020 | Insulins | Article

Islet pericytes convert into profibrotic myofibroblasts in a mouse model of islet vascular fibrosis

Authors: Luciana Mateus Gonçalves, Elizabeth Pereira, João Pedro Werneck de Castro, Ernesto Bernal-Mizrachi, Joana Almaça

Published in: Diabetologia | Issue 8/2020

Abstract

Aims/hypothesis

Islet vascular fibrosis may play an important role in the progression of type 2 diabetes, but there are no mouse models allowing detailed mechanistic studies to understand how a dysfunctional islet microvasculature contributes to diabetes pathogenesis. Here we report that the transgenic AktTg mouse, unlike other mouse strains, shows an increased deposition of extracellular matrix (ECM) proteins in perivascular regions, allowing us to study the cellular mechanisms that lead to islet vascular fibrosis.

Methods

Using immunohistochemistry, we labelled the islet microvasculature and ECM in pancreas sections of AktTg mice and human donors and performed lineage tracing to follow the fate of islet pericytes. We compared islet microvascular responses in living pancreas slices from wild-type and AktTg mice.

Results

We found that vascular pericytes proliferate extensively, convert into profibrotic myofibroblasts and substantially contribute to vascular fibrosis in the AktTg mouse model. The increased deposition of collagen I, fibronectin and periostin within the islet is associated with diminished islet perfusion as well as impaired capillary responses to noradrenaline (norepinephrine) and to high glucose in living pancreas slices.

Conclusions/interpretation

Our study thus illustrates how the AktTg mouse serves to elucidate a cellular mechanism in the development of islet vascular fibrosis, namely a change in pericyte phenotype that leads to vascular dysfunction. Because beta cells in the AktTg mouse are more numerous and larger, and secrete more insulin, in future studies we will test the role beta cell secretory products play in determining the phenotype of pericytes and other cells residing in the islet microenvironment under physiological and pathophysiological conditions.

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Title: Islet pericytes convert into profibrotic myofibroblasts in a mouse model of islet vascular fibrosis
Authors: Luciana Mateus Gonçalves
Elizabeth Pereira
João Pedro Werneck de Castro
Ernesto Bernal-Mizrachi
Joana Almaça
Publication date: 01-08-2020
Publisher: Springer Berlin Heidelberg
Keywords: Insulins
Insulins
Published in: Diabetologia / Issue 8/2020
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-020-05168-7

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