A heart-brain-spleen axis controls cardiac remodeling to hypertensive stress
Hypertensive heart disease (HTN-HD) meaningfully contributes to hypertension morbidity and mortality. Initially established as an adaptive response, HTN-HD progresses toward worsening of left ventricule (LV) function and heart failure (HF). Hypertensive stress elevates sympathetic nervous system (SNS) activity, a negative clinical predictor, and expands macrophages. How they interact in the compensatory phase of HTN-HD is unclear. We report that LV pressure overload recruited a brainstem neural circuit to enhance splenic SNS and induce placental growth factor (PlGF) secretion. During hypertensive stress, PlGF drove the proliferation of self-renewing cardiac resident macrophages (RMs) expressing its receptor neuropilin-1 (NRP1). Inhibition of the splenic neuroimmune axis or ablation of NRP1 in RM hindered the adaptive response to hypertensive stress, leading to HF. In humans, circulating PlGF correlated with cardiac hypertrophy, and failing hearts expressed NRP1 in RMs. Here, we discovered a multiorgan response driving a neural reflex to expand cardiac NRP1+ RM and counteract HF.
Authors
- T. Mikołajczyk (ORCID: https://orcid.org/0000-0002-7990-2896)
- Sarah‐Lena Puhl (ORCID: https://orcid.org/0000-0002-0556-5874)
- Agnese Migliaccio (ORCID: https://orcid.org/0000-0003-0500-6279)
- Francesco Mastroiacovo (ORCID: https://orcid.org/0000-0001-5704-8599)
- Marialuisa Perrotta (ORCID: https://orcid.org/0000-0002-0421-0721)
- Sara Nejat (ORCID: https://orcid.org/0000-0002-2374-5430)
- Sara Perrotta (ORCID: https://orcid.org/0000-0002-2903-3223)
- Bogusław Kapelak
- Giuseppe Lembo (ORCID: https://orcid.org/0000-0002-3510-223X)
- Valentina Fardella
- Raimondo Carnevale (ORCID: https://orcid.org/0000-0003-0249-8239)
- Lorenzo Carnevale (ORCID: https://orcid.org/0000-0002-6422-8253)
- Stefania Fardella (ORCID: https://orcid.org/0000-0002-1448-2165)
- Calum C. Bain (ORCID: https://orcid.org/0000-0001-8884-327X)
- Daniela Carnevale (ORCID: https://orcid.org/0000-0002-5016-3161)
- Fabio Pallante (ORCID: https://orcid.org/0000-0001-9224-6267)
- Slava Epelman (ORCID: https://orcid.org/0000-0003-3400-4475)
- Tomasz J Guzik (ORCID: https://orcid.org/0000-0003-2012-1187)
- Jacopo Pacella
- Giuseppe D’Agostino (ORCID: https://orcid.org/0000-0002-3502-4251)
- Azzurra Zonfrilli
Institutions
- Jagiellonian University (PL)
- University Health Network (CA)
- Manchester Academic Health Science Centre (GB)
- Toronto General Hospital (CA)
- University of Manchester (GB)
- Istituto Neurologico Mediterraneo (IT)
- Ted Rogers Centre for Heart Research (CA)
- Comprehensive Cancer Center Mainfranken (DE)
- Centre for Inflammation Research (GB)
- Ludwig-Maximilians-Universität München (DE)
- Sapienza University of Rome (IT)
- University of Edinburgh (GB)
Publication Details
- Journal
- Immunity
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1016/j.immuni.2025.02.013
- Citations
- 23
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 31.93
Funders
- Medical Research Council
- Biotechnology and Biological Sciences Research Council