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.
Keywords: AVM; BMP signaling.; HHT; cell cycle; mural cells; shear stress.
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