. 2025 Jul 16:10.1161/CIRCULATIONAHA.124.073630.

doi: 10.1161/CIRCULATIONAHA.124.073630. Online ahead of print.

PIEZO1 Overexpression in Hereditary Hemorrhagic Telangiectasia Arteriovenous Malformations

Hyojin Park^{1

2}, Sungwoon Lee¹, Jessica Furtado^{1

2}, Mark Robinson^{3

4}, Richard J Antaya⁵, S Paul Oh⁶, Young-Kwon Hong⁷, Martin A Schwartz^{1

8}, Lawrence H Young^{1

3}, Anne Eichmann^{1

2

9}

Affiliations

¹ Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT. (H.P., S.L., J.F., M.A.S., L.H.Y., A.E.).
² Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT. (H.P., J.F., A.E.).
³ Department of Internal Medicine, Section of Hematology and Medical Oncology, Yale University School of Medicine, New Haven, CT. (M.R., L.H.Y.).
⁴ Center of Molecular and Cellular Oncology, Yale University School of Medicine, New Haven, CT. (M.R.).
⁵ Departments of Dermatology, Pediatrics, and Nursing, Yale University School of Medicine, New Haven, CT. (R.J.A.).
⁶ Department of Translational Neuroscience, Barrow Aneurysm & AVM Research Center, Barrow Neurological Institute, Phoenix, AZ (S.P.O.).
⁷ Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles (Y.-K.H.).
⁸ Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT. (M.A.S.).
⁹ Université de Paris, PARCC, INSERM, Paris, France (A.E.).

PMID: 40665909
PMCID: PMC12270330 (available on 2026-07-16)
DOI: 10.1161/CIRCULATIONAHA.124.073630

PIEZO1 Overexpression in Hereditary Hemorrhagic Telangiectasia Arteriovenous Malformations

Hyojin Park et al. Circulation. 2025.

. 2025 Jul 16:10.1161/CIRCULATIONAHA.124.073630.

doi: 10.1161/CIRCULATIONAHA.124.073630. Online ahead of print.

Authors

Affiliations

¹ Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT. (H.P., S.L., J.F., M.A.S., L.H.Y., A.E.).
² Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT. (H.P., J.F., A.E.).
³ Department of Internal Medicine, Section of Hematology and Medical Oncology, Yale University School of Medicine, New Haven, CT. (M.R., L.H.Y.).
⁴ Center of Molecular and Cellular Oncology, Yale University School of Medicine, New Haven, CT. (M.R.).
⁵ Departments of Dermatology, Pediatrics, and Nursing, Yale University School of Medicine, New Haven, CT. (R.J.A.).
⁶ Department of Translational Neuroscience, Barrow Aneurysm & AVM Research Center, Barrow Neurological Institute, Phoenix, AZ (S.P.O.).
⁷ Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles (Y.-K.H.).
⁸ Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT. (M.A.S.).
⁹ Université de Paris, PARCC, INSERM, Paris, France (A.E.).

PMID: 40665909
PMCID: PMC12270330 (available on 2026-07-16)
DOI: 10.1161/CIRCULATIONAHA.124.073630

Abstract

Background: Hereditary hemorrhagic telangiectasia is an inherited vascular disorder characterized by arteriovenous malformations (AVMs). Loss-of-function variations in activin receptor-like kinase 1 (ALK1) cause type 2 hereditary hemorrhagic telangiectasia, and Alk1 knockout mice develop AVMs, along with overactivation of vascular endothelial growth factor receptor 2/phosphoinositide 3-kinase/AKT signaling. The full spectrum of signaling alterations resulting from ALK1 variations remains unknown, and more effective and specific inhibitors to combat AVM formation in patients are needed.

Methods: Single-cell RNA sequencing of endothelial-specific Alk1 knockout mouse retinas and controls was performed. Overexpression of fluid shear stress signaling signatures including the mechanosensitive ion channel PIEZO1 was confirmed in mouse and human type 2 hereditary hemorrhagic telangiectasia lesions. Genetic and pharmacological PIEZO1 inhibition was tested in Alk1 knockout mice, along with downstream PIEZO1 signaling.

Results: A cluster of Alk1 mutant endothelial cells with altered arterio-venous identity overexpressed pathways related to fluid shear stress, hypoxia, inflammation, cell cycle, and vascular endothelial growth factor receptor 2/phosphoinositide 3-kinase/AKT signaling. Piezo1 deletion and pharmacological inhibition in Alk1-deficient mice mitigated AVM formation, whereas Piezo1 overexpression enhanced AVM formation induced by ALK1 ligand blockade. Mechanistically, PIEZO1 inhibition reduced elevated vascular endothelial growth factor receptor 2/AKT, ERK5-p62-KLF4, endothelial nitric oxide synthase, hypoxia, proliferation, and inflammation in ALK1-deficient endothelium.

Conclusions: PIEZO1 expression and signaling are elevated in type 2 hereditary hemorrhagic telangiectasia. PIEZO1 blockade reduces AVM formation and alleviates cellular and molecular hallmarks of ALK1-deficient cells. This finding provides new insights into the mechanistic underpinnings of ALK1-related vascular diseases and identifies potential therapeutic targets to prevent AVMs.

Keywords: ALK1; PIEZO1 protein, mouse; arteriovenous malformations; mechanotransduction, cellular; telangiectasia, hereditary hemorrhagic.

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Update of

PIEZO1 overexpression in hereditary hemorrhagic telangiectasia arteriovenous malformations.
Park H, Lee S, Furtado J, Robinson M, Schwartz M, Young L, Eichmann A. Park H, et al. bioRxiv [Preprint]. 2024 Nov 28:2024.11.27.625696. doi: 10.1101/2024.11.27.625696. bioRxiv. 2024. Update in: Circulation. 2025 Jul 16. doi: 10.1161/CIRCULATIONAHA.124.073630. PMID: 39651206 Free PMC article. Updated. Preprint.

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PIEZO1 Overexpression in Hereditary Hemorrhagic Telangiectasia Arteriovenous Malformations

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PIEZO1 Overexpression in Hereditary Hemorrhagic Telangiectasia Arteriovenous Malformations

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