Cell Reports (Jul 2024)
Macrophages preserve endothelial cell specialization in the adrenal gland to modulate aldosterone secretion and blood pressure
- Zheng Fan,
- Mara Karakone,
- Shunmugam Nagarajan,
- Nadine Nagy,
- Wiebke Mildenberger,
- Ekaterina Petrova,
- Laura Catharina Hinte,
- Mitchell Bijnen,
- Philipp Häne,
- Eric Nelius,
- Jing Chen,
- Irina Ferapontova,
- Ferdinand von Meyenn,
- Francesco Trepiccione,
- Mesut Berber,
- David Penton Ribas,
- Anne Eichmann,
- Maria-Christina Zennaro,
- Norihiko Takeda,
- Jens W. Fischer,
- Ariadni Spyroglou,
- Martin Reincke,
- Felix Beuschlein,
- Johannes Loffing,
- Melanie Greter,
- Christian Stockmann
Affiliations
- Zheng Fan
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland; Corresponding author
- Mara Karakone
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
- Shunmugam Nagarajan
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
- Nadine Nagy
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Wiebke Mildenberger
- University of Zurich, Institute for Experimental Immunology, 8057 Zurich, Switzerland
- Ekaterina Petrova
- University of Zurich, Institute for Experimental Immunology, 8057 Zurich, Switzerland
- Laura Catharina Hinte
- Laboratory of Nutrition and Metabolic Epigenetics, Institute for Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
- Mitchell Bijnen
- University of Zurich, Institute for Experimental Immunology, 8057 Zurich, Switzerland
- Philipp Häne
- University of Zurich, Institute for Experimental Immunology, 8057 Zurich, Switzerland
- Eric Nelius
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
- Jing Chen
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
- Irina Ferapontova
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
- Ferdinand von Meyenn
- Laboratory of Nutrition and Metabolic Epigenetics, Institute for Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
- Francesco Trepiccione
- Department of Translational Medical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
- Mesut Berber
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
- David Penton Ribas
- Electrophysiology Facility (e-phac), Department of Molecular Life Sciences, University of Zurich (UZH), 8057 Zürich, Switzerland
- Anne Eichmann
- Cardiovascular Research Center and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
- Maria-Christina Zennaro
- INSERM U970, Paris Cardiovascular Research Center, Paris, France
- Norihiko Takeda
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan
- Jens W. Fischer
- Institute of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
- Ariadni Spyroglou
- Klinik für Endokrinologie, Diabetologie, und Klinische Ernährung, UniversitätsSpital Zürich (USZ) and UZH, Raemistrasse 100, 8091 Zurich, Switzerland; Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University (LMU), Munich, Germany
- Martin Reincke
- Klinik für Endokrinologie, Diabetologie, und Klinische Ernährung, UniversitätsSpital Zürich (USZ) and UZH, Raemistrasse 100, 8091 Zurich, Switzerland
- Felix Beuschlein
- Klinik für Endokrinologie, Diabetologie, und Klinische Ernährung, UniversitätsSpital Zürich (USZ) and UZH, Raemistrasse 100, 8091 Zurich, Switzerland; Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University (LMU), Munich, Germany
- Johannes Loffing
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland
- Melanie Greter
- University of Zurich, Institute for Experimental Immunology, 8057 Zurich, Switzerland
- Christian Stockmann
- University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland; INSERM U970, Paris Cardiovascular Research Center, Paris, France; Corresponding author
- Journal volume & issue
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Vol. 43,
no. 7
p. 114395
Abstract
Summary: Macrophages play crucial roles in organ-specific functions and homeostasis. In the adrenal gland, macrophages closely associate with sinusoidal capillaries in the aldosterone-producing zona glomerulosa. We demonstrate that macrophages preserve capillary specialization and modulate aldosterone secretion. Using macrophage-specific deletion of VEGF-A, single-cell transcriptomics, and functional phenotyping, we found that the loss of VEGF-A depletes PLVAP+ fenestrated endothelial cells in the zona glomerulosa, leading to increased basement membrane collagen IV deposition and subendothelial fibrosis. This results in increased aldosterone secretion, called “haptosecretagogue” signaling. Human aldosterone-producing adenomas also show capillary rarefaction and basement membrane thickening. Mice with myeloid cell-specific VEGF-A deletion exhibit elevated serum aldosterone, hypokalemia, and hypertension, mimicking primary aldosteronism. These findings underscore macrophage-to-endothelial cell signaling as essential for endothelial cell specialization, adrenal gland function, and blood pressure regulation, with broader implications for other endocrine organs.
