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Embryological cellular origins and hypoxia-mediated mechanisms in PIK3CA-driven refractory vascular malformations

Torii, Sota ; Nagaharu, Keiki LU orcid ; Nakanishi, Nanako ; Usui, Hidehito ; Hori, Yumiko ; Hirose, Katsutoshi ; Toyosawa, Satoru ; Morii, Eiichi ; Narushima, Mitsunaga and Kubota, Yoshiaki , et al. (2025) In EMBO Molecular Medicine 17(6). p.1289-1324
Abstract

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 Pik3caH1047R in the CPM. Mice expressing Pik3caH1047R in the CPM developed vascular abnormalities restricted to the head and neck. Single-cell RNA sequencing revealed that... (More)

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 Pik3caH1047R in the CPM. Mice expressing Pik3caH1047R in the CPM developed vascular abnormalities restricted to the head and neck. Single-cell RNA sequencing revealed that Pik3caH1047R 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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cardiopharyngeal Mesoderm, Endothelial Cellular Origin, Hypoxia, PIK3CA Mutation, Vascular Malformations
in
EMBO Molecular Medicine
volume
17
issue
6
pages
1289 - 1324
publisher
Wiley-Blackwell
external identifiers
  • scopus:105002620224
  • pmid:40234712
ISSN
1757-4676
DOI
10.1038/s44321-025-00235-1
language
English
LU publication?
no
additional info
Publisher Copyright: © The Author(s) 2025.
id
fc004172-dbd6-4666-b1b6-9ca5e79d98c7
date added to LUP
2025-12-23 09:20:02
date last changed
2025-12-24 03:00:04
@article{fc004172-dbd6-4666-b1b6-9ca5e79d98c7,
  abstract     = {{<p>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.</p>}},
  author       = {{Torii, Sota and Nagaharu, Keiki and Nakanishi, Nanako and Usui, Hidehito and Hori, Yumiko and Hirose, Katsutoshi and Toyosawa, Satoru and Morii, Eiichi and Narushima, Mitsunaga and Kubota, Yoshiaki and Nakagawa, Osamu and Imanaka-Yoshida, Kyoko and Maruyama, Kazuaki}},
  issn         = {{1757-4676}},
  keywords     = {{Cardiopharyngeal Mesoderm; Endothelial Cellular Origin; Hypoxia; PIK3CA Mutation; Vascular Malformations}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{6}},
  pages        = {{1289--1324}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{EMBO Molecular Medicine}},
  title        = {{Embryological cellular origins and hypoxia-mediated mechanisms in PIK3CA-driven refractory vascular malformations}},
  url          = {{http://dx.doi.org/10.1038/s44321-025-00235-1}},
  doi          = {{10.1038/s44321-025-00235-1}},
  volume       = {{17}},
  year         = {{2025}},
}