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
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.
