EphrinA4/EphA4 controls blood pressure via arterial sympathetic innervation in male mice

The autonomic sympathetic nervous system innervates peripheral resistance arteries, thereby controlling arterial diameter and modulating blood supply to organs and arterial tone. Despite its fundamental role in blood flow regulation and cardiovascular adaptation to challenging situations, how sympathetic arterial innervation develops remains poorly understood. We here show that sympathetic arterial innervation is regulated by the axonal guidance molecule EphrinA4 in arterial Smooth Muscle Cells (SMCs), which repels sympathetic axons via the EphA4 receptor.

Using the EphA4flox-THCRE mouse, we specifically inactivated EphA4 in sympathetic axons, inducing a loss of repulsion and increased sympathetic innervation of peripheral arteries throughout life. Functional consequences included a significant increase in arterial tone, including resistivity and vasoconstriction, associated with elevated systemic arterial blood pressure at rest and a marked increase during acute stress. These findings identify a pathway that negatively regulates sympathetic arterial innervation and could contribute to elevated systemic blood pressure in male mice.

We would like to thank Adrien Flahault, Michel Azizi and Catherine Llaurens Cortes for insightful discussion; Guy Malkinson for critical reading of the manuscript, and Bing-Cheng Wang for providing EphrinAs TKO mice tissues and Cecile Duplaa for sharing data. This work was supported by grants from Inserm, Agence Nationale de la Recherche (ANR NIRVANA) and Fondation pour la Recherche Médicale (FRM). We gratefully acknowledge support by Ligue contre le Cancer and MemoLife Labex (ST), FRM (ES).

These authors contributed equally: Emilie Simonnet, Sabrina Martin. Center for Interdisciplinary Research in Biology (CIRB), College de France, UMR INSERM 1050, CNRS 7241, Université PSL, F-75005, Paris, France Emilie Simonnet, Sabrina Martin, Virginie Monceau, Gaëtan Pallot, Sonia Taib & Isabelle Brunet Paris Centre de Recherche Cardiovasculaire (PARCC), Université de Paris, INSERM 970, F-75015, Paris, France José Vilar, Luc Pardanaud, Anne Eichmann & Jean-Sébastien Silvestre Radiotoxicology and Radiobiology Research Laboratory (LRTOX), French Authority for Nuclear Safety and Radiation Protection (ASNR), F-92260, Fontenay-aux-roses, France Mitochondrial and Cardiovascular Physiopathology (MITOVASC), Université d’Angers, UMR INSERM 1083, CNRS 6015, Université d’Angers, F-49000, Angers, France Nantes Université, CNRS, INSERM, l’institut du thorax, F-44000, Nantes, France Animal Behavioral Platform (SCAC), US INSERM 51, UAR CNRS 2026, HeRacLeS, Institute for Research and Innovation in Biomedicine (IRIB), UFR Santé, Université de Rouen Normandie, F-76000, Rouen, France Jean-Claude do Rego, Jean-Luc do Rego & Colin Salaün Physiologie et médecine expérimentale du cœur et des muscles (PhyMedExp), UMR INSERM 1046, CNRS 9214, F-34000, Montpellier, France Centre de Recherche des Cordeliers (CRC), UMR INSERM 1138, CNRS 8228, Université de Paris, Sorbonne Université, F-75006, Paris, France The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.

If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Simonnet, E., Martin, S., Vilar, J. et al.