Embryological cellular origins and hypoxia-mediated mechanisms in PIK3CA-driven refractory vascular malformations
Congenital vascular malformations, affecting 0.5% of the population, often occur in the head and neck, complicating treatment due to the critical functions in these regions. Our previous research identified distinct developmental origins for blood and lymphatic vessels in these areas, tracing them to the cardiopharyngeal mesoderm (CPM), which contributes to the development of the head, neck, and cardiovascular system in both mouse and human embryos. In this study, we investigated the pathogenesis of these malformations by expressing Pik3ca<sup>H1047R</sup> in the CPM. Mice expressing Pik3ca<sup>H1047R</sup> in the CPM developed vascular abnormalities restricted to the head and neck. Single-cell RNA sequencing revealed that Pik3ca<sup>H1047R</sup> upregulates Vegf-a expression in endothelial cells through HIF-mediated hypoxia signaling. Human samples supported these findings, showing elevated HIF-1α and VEGF-A in malformed vessels. Notably, inhibition of HIF-1α and VEGF-A in the mouse model significantly reduced abnormal vasculature. These results highlight the role of embryonic origins and hypoxia-driven mechanisms in vascular malformations, providing a foundation for the development of therapies targeting these difficult-to-treat conditions.
Authors
- Mitsunaga Narushima (ORCID: https://orcid.org/0000-0001-7631-301X)
- Yoshiaki Kubota (ORCID: https://orcid.org/0000-0001-6672-4122)
- Keiki Nagaharu (ORCID: https://orcid.org/0000-0002-6139-4256)
- Hidehito Usui (ORCID: https://orcid.org/0000-0002-3308-9959)
- Eiichi Morii (ORCID: https://orcid.org/0000-0001-8490-3650)
- Satoru Toyosawa (ORCID: https://orcid.org/0000-0002-0338-0251)
- Katsutoshi Hirose (ORCID: https://orcid.org/0000-0003-4148-1106)
- Kazuaki Maruyama (ORCID: https://orcid.org/0000-0002-3935-328X)
- Nagako Nakanishi
- Sota Torii
- Osamu Nakagawa (ORCID: https://orcid.org/0000-0002-3858-6903)
- Kyoko Imanaka-Yoshida (ORCID: https://orcid.org/0000-0002-9147-4169)
- Yumiko Hori
Institutions
- Mie University (JP)
- Osaka National Hospital (JP)
- Keio University Hospital (JP)
- National Cerebral and Cardiovascular Center (JP)
- Kanagawa Children's Medical Center (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-04-15
- DOI
- https://doi.org/10.1038/s44321-025-00235-1
- Citations
- 3
- Primary Topic
- Vascular Malformations and Hemangiomas
- Type
- article
- Field-Weighted Citation Impact
- 6.02
Funders
- Takeda Science Foundation
- Sumitomo Foundation
- Japan Foundation for Applied Enzymology
- Japan Agency for Medical Research and Development
- Kurata Memorial Hitachi Science and Technology Foundation
- Japan Intractable Diseases Research Foundation
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- SENSHIN Medical Research Foundation
- Terumo Foundation for Life Sciences and Arts
- Japan Society for the Promotion of Science