Islet vascularization is regulated by primary endothelial cilia via VEGF-A dependent signaling
- Karolinska Institute, Sweden
- Helmholtz Zentrum München, Germany
- Karolinska Institutet, Sweden
Abstract
Islet vascularization is essential for intact islet function and glucose homeostasis. We have previously shown that primary cilia directly regulate insulin secretion. However, it remains unclear whether they are also implicated in islet vascularization. At eight weeks, murine Bbs4‑/- islets show significantly lower intra-islet capillary density with enlarged diameters. Transplanted Bbs4-/- islets exhibit delayed re-vascularization and reduced vascular fenestration after engraftment, partially impairing vascular permeability and glucose delivery to b-cells. We identified primary cilia on endothelial cells as the underlying cause of this regula tion, via the vascular endothelial growth factor A (VEGF-A)/VEGF receptor 2 (VEGFR2) pathway. In vitro silencing of ciliary genes in endothelial cells disrupts VEGF-A/VEGFR2 internalization and downstream signaling. Consequently, key features of angiogenesis including proliferation and migration are attenuated in human BBS4 silenced endothelial cells. We conclude that endothelial cell primary cilia regulate islet vascularization and vascular barrier function via the VEGF-A/VEGFR2 signaling pathway.
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All data generated or analyzed during this study are included in this mansucript and supporting files.
Article and author information
Author details
Jantje Mareike Gerdes
Funding
Deutsches Zentrum fuer Diabetesforschung
- Jantje Mareike Gerdes
Berth von Kantzows Stiftelse
- Per-Olof Berggren
Skandia Insurance Company Ltd
- Per-Olof Berggren
ERC (ERC-2018-AdG 834860 EYELETS)
- Per-Olof Berggren
FP7 People: Marie-Curie Actions (International Reintegration Grant PIRG07-GA-2010-268397)
- Jantje Mareike Gerdes
Swedish Research Council
- Per-Olof Berggren
Novo Nordisk Fonden
- Per-Olof Berggren
Karolinska Institutet
- Yan Xiong
Swedish Strategic Research Program Diabetes
- Per-Olof Berggren
Swedish Diabetes Association
- Per-Olof Berggren
Family Knut och Alice Wallenberg Foundation
- Per-Olof Berggren
Diabetes Research Wellness Foundation
- Per-Olof Berggren
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance to the German and Swedish animal welfare legislation. Experimental procedures involving live animals were carried out in accordance with animal welfare regulations and with approval of the Regierung Oberbayern (Az 55.2-1-54-2532-187-15 and ROB-55.2-2532.Vet_02-14-157) or in accordance with the Karolinska Institutet's guidelines for the care and use of animals in research, and were approved by the institute's Animal Ethics Committee respectively (Ethical permit number 19462-2017).
Copyright
© 2020, Xiong et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Islet vascularization is regulated by primary endothelial cilia via VEGF-A dependent signaling
eLife 9:e56914.
https://doi.org/10.7554/eLife.56914
