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) vascular disorder. Yet, how flow-dependent cell cycle regulation intersects with mural cell remodeling in HHT remains unclear. Methods: 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: . 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.