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. The sympathetic nervous system regulates blood pressure, but how arterial sympathetic innervation is established remains unclear. Here, the authors show that EphrinA4/EphA4 signalling limits sympathetic arterial innervation, thereby controlling vascular resistance and systemic blood pressure.
Authors
- Nadine Bouby (ORCID: https://orcid.org/0000-0002-2338-9480)
- Luc Pardanaud (ORCID: https://orcid.org/0000-0002-7358-6730)
- Colin Salaün (ORCID: https://orcid.org/0000-0002-7414-335X)
- Anne Eichmann (ORCID: https://orcid.org/0000-0001-5563-210X)
- Anne-Clémence Vion (ORCID: https://orcid.org/0000-0002-2788-2512)
- José Vilar (ORCID: https://orcid.org/0000-0002-9136-7726)
- Emilie Vessières (ORCID: https://orcid.org/0009-0000-9017-6349)
- Virginie Monceau (ORCID: https://orcid.org/0000-0002-1717-8935)
- G Pallot (ORCID: https://orcid.org/0000-0001-7961-0685)
- Émilie Simonnet
- Sonia Taïb (ORCID: https://orcid.org/0000-0002-9981-5204)
- Marc Rio (ORCID: https://orcid.org/0000-0002-2751-3653)
- Isabelle Brunet (ORCID: https://orcid.org/0000-0002-5490-2937)
- Dominique Laude (ORCID: https://orcid.org/0000-0003-3097-9849)
- Sabrina Martín (ORCID: https://orcid.org/0000-0001-9511-8316)
- Jean‐Sébastien Silvestre (ORCID: https://orcid.org/0000-0003-3962-2205)
- Fabrice Raynaud (ORCID: https://orcid.org/0000-0003-3055-0524)
- Daniel Henrion (ORCID: https://orcid.org/0000-0003-1094-0285)
- Jean-Claude do Rego
- Jean-Luc do Rego
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Sorbonne Université (FR)
- Physiologie et Médecine Expérimentale du Coeur et des Muscles (FR)
- Centre de Recherche des Cordeliers (FR)
- Centre Interdisciplinaire de Recherche en Biologie (FR)
- Paris Cardiovascular Research Center (FR)
- Institute for Research and Innovation in Biomedicine (FR)
- Institut du Thorax (FR)
- Institut de Radiobiologie Cellulaire et Moléculaire (FR)
- Université d'Angers (FR)
- Université de Rouen Normandie (FR)
- Nantes Université (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-10-14
- DOI
- https://doi.org/10.1038/s41467-026-78388-x
- Primary Topic
- Blood Pressure and Hypertension Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Ligue Contre le Cancer