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 C. 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, Martín Reincke, Felix Beuschlein, Johannes Loffing, Melanie Greter, Christian Stockmann
Abstract
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.