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Flow-induced Klf4-Akt signaling links EC cycling to mural cell defects in arterial-venous malformations

Fluid shear stress (FSS) safeguards vascular homeostasis, coordinating endothelial cell (EC) behavior and endothelial - mural cell communication. Disrupted flow sensing driving excessive proliferation contribute to arterial-venous malformations (AVMs) in Hereditary Hemorrhagic Telangiectasia (HHT) v...

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Hauptverfasser: Lin, Yanzhu (Verfasst von) , Hashemi, Zohrah (Verfasst von) , Zhang, Qing (Verfasst von) , Di, Yuxi (Verfasst von) , Behera, Tanmaya (Verfasst von) , Gahn, Johannes (Verfasst von) , Banerjee, Kuheli (Verfasst von) , Wu, Fan (Verfasst von) , Andorfer, Kornelia (Verfasst von) , Singhal, Mahak (Verfasst von) , Seebauer, Caroline (Verfasst von) , Ola, Roxana (Verfasst von)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2026-2-26
In: Theranostics
Year: 2026, Jahrgang: 16, Heft: 9, Pages: 4905-4922
ISSN:1838-7640
DOI:10.7150/thno.121154
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.7150/thno.121154
Verlag, kostenfrei, Volltext: https://www.thno.org/v16p4905.htm
Volltext
Verfasserangaben:Yanzhu Lin, Zohrah Hashemi, Qing Zhang, Yuxi Di, Tanmaya Behera, Johannes Gahn, Kuheli Banerjee, Fan Wu, Kornelia Andorfer, Mahak Singhal, Caroline Seebauer, Roxana Ola
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Zusammenfassung:Fluid shear stress (FSS) safeguards vascular homeostasis, coordinating endothelial cell (EC) behavior and endothelial - mural cell communication. Disrupted flow sensing driving excessive proliferation contribute to arterial-venous malformations (AVMs) in Hereditary Hemorrhagic Telangiectasia (HHT) vascular disorder. Yet, how flow-dependent cell cycle regulation intersects with mural cell remodeling in HHT remains unclear. Methods: We used a combination between in vitro shear stress assays and in vivo analyses of multiple murine HHT models, including endothelial-specific loss of Activin-like kinase 1 (Alk1) or Smad4 and bone morphogenic factor 9/10 (BMP9/10) ligand blockade. Retinal vasculature and human nasal mucosal biopsies from HHT2 patients were examined for pathway conservation. Endothelial - mural cell crosstalk was evaluated using transwell and three-dimensional flow-dependent co-culture assays. Loss and gain of function studies were employed to define disease mechanisms. Results: Across all studied murine HHT models and in HHT2 telangiectasias, AVM endothelium exhibited excessive flow-induced Krüpper-like 4 (KLF4) - Akt pathway activation, sustained EC proliferation, and abolition of FSS-mediated cyclin-dependent kinases 2/6 (CDK2/6) inhibition. The hyperproliferative state suppressed the expression of endothelial platelet-derived growth factor B (PDGFB) leading to pericyte loss, and and mural cell remodeling in AVMs. Restoration of endothelial quiescence via inhibition of KLF4, Akt or CDK4/6 rescued FSS-induced PDGFB expression. Pharmacological PDGFB induction with thalidomide restored mural cell coverage, and significantly reduced AVM burden in vivo. Conclusion: Our study establishes EC cycle state as the upstream determinant of mural cell stability under pathological flow and provides the mechanistic reasoning for why distinct therapeutic strategies (e.g., CDK4/6 inhibition, Akt modulation, or thalidomide-induced PDGFB upregulation) converge on AVM stabilization.
Beschreibung:Gesehen am 07.04.2026
Beschreibung:Online Resource
ISSN:1838-7640
DOI:10.7150/thno.121154

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