Islet vascularization is regulated by primary endothelial cilia via VEGF-A dependent signaling

  1. Yan Xiong
  2. M Julia Scerbo
  3. Anett Seelig
  4. Francesco Volta
  5. Nils O'Brien
  6. Andrea Dicker
  7. Daniela Padula
  8. Heiko Lickert
  9. Jantje Mareike Gerdes  Is a corresponding author
  10. Per-Olof Berggren
  1. Karolinska Institute, Sweden
  2. Helmholtz Zentrum München, Germany
  3. 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.

Data availability

All data generated or analyzed during this study are included in this mansucript and supporting files.

Article and author information

Author details

  1. Yan Xiong

    Rolf Luft Center for endocrinology and diabetes, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2339-130X
  2. M Julia Scerbo

    Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Anett Seelig

    Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Francesco Volta

    Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Nils O'Brien

    Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Andrea Dicker

    Rolf Luft Center for Endocrinology and Diabetes, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  7. Daniela Padula

    Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Heiko Lickert

    Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Jantje Mareike Gerdes

    Institute for Diabetes and Regeneration Research, Helmholtz Zentrum München, Garching, Germany
    For correspondence
    jantje.gerdes@helmholtz-muenchen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6885-5441
  10. Per-Olof Berggren

    Rolf Luft Center for endocrinology and diabetes, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

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.

Metrics

  • 3,001
    views
  • 431
    downloads
  • 25
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Yan Xiong
  2. M Julia Scerbo
  3. Anett Seelig
  4. Francesco Volta
  5. Nils O'Brien
  6. Andrea Dicker
  7. Daniela Padula
  8. Heiko Lickert
  9. Jantje Mareike Gerdes
  10. Per-Olof Berggren
(2020)
Islet vascularization is regulated by primary endothelial cilia via VEGF-A dependent signaling
eLife 9:e56914.
https://doi.org/10.7554/eLife.56914

Share this article

https://doi.org/10.7554/eLife.56914

Further reading

    1. Cell Biology
    Zewei Zhao, Longyun Hu ... Zhonghan Yang
    Research Article

    The induction of adipose thermogenesis plays a critical role in maintaining body temperature and improving metabolic homeostasis to combat obesity. β3-adrenoceptor (β3-AR) is widely recognized as a canonical β-adrenergic G-protein-coupled receptor (GPCR) that plays a crucial role in mediating adipose thermogenesis in mice. Nonetheless, the limited expression of β3-AR in human adipocytes restricts its clinical application. The objective of this study was to identify a GPCR that is highly expressed in human adipocytes and to explore its potential involvement in adipose thermogenesis. Our research findings have demonstrated that the adhesion G-protein-coupled receptor A3 (ADGRA3), an orphan GPCR, plays a significant role in adipose thermogenesis through its constitutively active effects. ADGRA3 exhibited high expression levels in human adipocytes and mouse brown fat. Furthermore, the knockdown of Adgra3 resulted in an exacerbated obese phenotype and a reduction in the expression of thermogenic markers in mice. Conversely, Adgra3 overexpression activated the adipose thermogenic program and improved metabolic homeostasis in mice without exogenous ligand. We found that ADGRA3 facilitates the biogenesis of beige human or mouse adipocytes in vitro. Moreover, hesperetin was identified as a potential agonist of ADGRA3, capable of inducing adipocyte browning and ameliorating insulin resistance in mice. In conclusion, our study demonstrated that the overexpression of constitutively active ADGRA3 or the activation of ADGRA3 by hesperetin can induce adipocyte browning by Gs-PKA-CREB axis. These findings indicate that the utilization of hesperetin and the selective overexpression of ADGRA3 in adipose tissue could serve as promising therapeutic strategies in the fight against obesity.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Bethany M Bartlett, Yatendra Kumar ... Wendy A Bickmore
    Research Article Updated

    During oncogene-induced senescence there are striking changes in the organisation of heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory gene expression programme – the senescence-associated secretory phenotype (SASP) – driven by transcription factors such as NF-κB. The relationship between heterochromatin re-organisation and the SASP has been unclear. Here, we show that TPR, a protein of the nuclear pore complex basket required for heterochromatin re-organisation during senescence, is also required for the very early activation of NF-κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of innate immune signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. We show that HMGA1 is also required for cytoplasmic chromatin fragment formation. Together these data suggest that re-organisation of heterochromatin is involved in altered structural integrity of the nuclear periphery during senescence, and that this can lead to activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP.