Endothelial cell mineralocorticoid receptors oppose VEGF-induced gene expression and angiogenesis

in Journal of Endocrinology
Authors:
Achim Lother Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Search for other papers by Achim Lother in
Current site
Google Scholar
PubMed Close
,
Lisa Deng Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Search for other papers by Lisa Deng in
Current site
Google Scholar
PubMed Close
,
Michael Huck Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Search for other papers by Michael Huck in
Current site
Google Scholar
PubMed Close
,
David Fürst Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Search for other papers by David Fürst in
Current site
Google Scholar
PubMed Close
,
Jessica Kowalski Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Search for other papers by Jessica Kowalski in
Current site
Google Scholar
PubMed Close
,
Jennifer S Esser Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Search for other papers by Jennifer S Esser in
Current site
Google Scholar
PubMed Close
,
Martin Moser Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Search for other papers by Martin Moser in
Current site
Google Scholar
PubMed Close
,
Christoph Bode Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Search for other papers by Christoph Bode in
Current site
Google Scholar
PubMed Close
, and
Lutz Hein Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany

Search for other papers by Lutz Hein in
Current site
Google Scholar
PubMed Close

Correspondence should be addressed to A Lother: achim.lother@universitaets-herzzentrum.de
DOI:
https://doi.org/10.1530/JOE-18-0494
Volume/Issue:
Volume 240: Issue 1
Article Type:
Research Article
Page Range:
15–26
Online Publication Date:
Jan 2019
Copyright:
© 2018 Society for Endocrinology 2018
Restricted access
Rent on DeepDyve

Sign up for journal news

Aldosterone is a key factor in adverse cardiovascular remodeling by acting on the mineralocorticoid receptor (MR) in different cell types. Endothelial MR activation mediates hypertrophy, inflammation and fibrosis. Cardiovascular remodeling is often accompanied by impaired angiogenesis, which is a risk factor for the development of heart failure. In this study, we evaluated the impact of MR in endothelial cells on angiogenesis. Deoxycorticosterone acetate (DOCA)-induced hypertension was associated with capillary rarefaction in the heart of WT mice but not of mice with cell type-specific MR deletion in endothelial cells. Consistently, endothelial MR deletion prevented the inhibitory effect of aldosterone on the capillarization of subcutaneously implanted silicon tubes and on capillary sprouting from aortic ring segments. We examined MR-dependent gene expression in cultured endothelial cells by RNA-seq and identified a cluster of differentially regulated genes related to angiogenesis. We found opposing effects on gene expression when comparing activation of the mineralocorticoid receptor in ECs to treatment with vascular endothelial growth factor (VEGF), a potent activator of angiogenesis. In conclusion, we demonstrate here that activation of endothelial cell MR impaired angiogenic capacity and lead to capillary rarefaction in a mouse model of MR-driven hypertension. MR activation opposed VEGF-induced gene expression leading to the dysregulation of angiogenesis-related gene networks in endothelial cells. Our findings underscore the pivotal role of endothelial cell MR in the pathophysiology of hypertension and related heart disease.

Supplementary Materials

    • Supplemental table S1: Primer sequences
    • Supplemental table S2: ALDO up- or downregulated genes
    • Supplemental table S3: MR knockdown up- or downregulated genes
    • Supplemental Figure S1: Putative MR target genes in endothelial cells. The promoter region (2kb from transcription start site) of ALDO-induced or –repressed genes was screened for enrichment of transcription factor binding motifs (A). mRNA expression of ALDO up- or downregulated genes containing a mineralocorticoid receptor binding motif in their promoter region was derived from RNAseq (B, mean, n =3 per group, *q<0.05, **q<0.01, ***q<0.001).
    • Supplemental Figure S2: Impact of MR knockdown on gene expression in endothelial cells. We identified biological processes enriched (P<0.01) among genes that were up- or downregulated in solvent- and aldosterone-treated siMR vs. siCTRL (q < 0.05) using ClueGO.

Journal of Endocrinology is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 672 431 0
PDF Downloads 458 249 0

 

  • Collapse
  • Expand
Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2018 Society for Endocrinology 2018
Page(s):
12
Article Type:
Research Article
Received Date:
17 Sep 2018
Accepted Date:
17 Sep 2018
Print Publication Date:
01 Jan 2019
Online Publication Date:
Jan 2019
Keywords:
endothelial cells; mineralocorticoid receptor; aldosterone; angiogenesis; hypertension