Endothelial soluble APP/APLP2 promote heart repair through KIT-mediated angiogenesis
Amyloid precursor protein (APP) gives rise to amyloid-β, a pathological factor in Alzheimer's disease. However, the physiological role of APP and its homolog amyloid precursor-like protein 2 (APLP2), which are also widely expressed outside the nervous system, is largely unknown. Here, we show that endothelial APP and APLP2 are required for postischemia angiogenesis after myocardial infarction (MI). We found that hypoxia induced the endothelial expression of α-secretases, resulting in nonamyloidogenic processing of APP and APLP2 into the soluble forms APPsα and APLP2sα. Loss of endothelial APP and APLP2 led to decreased neovascularization as well as increased heart failure and mortality after MI, a phenotype that could be rescued by endothelial expression of APPsα. APPsα and APLP2sα exerted their proangiogenic effect by positive allosteric modulation of the endothelial receptor tyrosine kinase KIT, which promotes postischemia neovascularization. Our data identify a function of APP and APLP2 in endothelial cells, which is required for postischemia tissue repair, and suggest approaches to improve regeneration after MI and other ischemic diseases.
Authors
- Shangmin Liu
- Sabrina Kurz
- Paula Sofía Yunes-Leites (ORCID: https://orcid.org/0000-0003-3438-1115)
- Ulrike Müller (ORCID: https://orcid.org/0000-0002-5965-3642)
- Niharika Shiva
- Kenneth Anthony Roquid (ORCID: https://orcid.org/0000-0001-8659-3465)
- Nina Wettschureck (ORCID: https://orcid.org/0000-0001-6858-1460)
- Kenny Mattonet (ORCID: https://orcid.org/0000-0002-9705-8086)
- Rémy Bonnavion (ORCID: https://orcid.org/0000-0002-7389-4282)
- Marija Banićević
- Guozheng Liang (ORCID: https://orcid.org/0000-0003-3335-0915)
- Haruya Kawase (ORCID: https://orcid.org/0000-0002-8927-0896)
- Mario Looso (ORCID: https://orcid.org/0000-0003-1495-9530)
- Young‐June Jin (ORCID: https://orcid.org/0000-0002-4649-8890)
- Stefan Offermanns (ORCID: https://orcid.org/0000-0001-8676-6805)
- Haaglim Cho (ORCID: https://orcid.org/0000-0002-6577-5320)
- Verena Bengelsdorff
- S Dimmeler
- Lukas Tombor (ORCID: https://orcid.org/0000-0002-5867-576X)
- Stefan Günther (ORCID: https://orcid.org/0000-0002-5594-4549)
Institutions
- Goethe University Frankfurt (DE)
- Heidelberg University (DE)
- Frankfurt Institute for Advanced Studies (DE)
- Nagoya University Hospital (JP)
- Max Planck Institute for Heart and Lung Research (DE)
- German Center for Infection Research (DE)
- German Centre for Cardiovascular Research (DE)
- Nagoya University (JP)
Publication Details
- Journal
- Science Advances
- Published
- 2026-05-22
- DOI
- https://doi.org/10.1126/sciadv.aeh0301
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Japan Society for the Promotion of Science