Flow-induced Klf4-Akt signaling links EC cycling to mural cell defects in arterial-venous malformations - PubMed
12 hours ago
- #AVM
- #HHT
- #shear stress
- Fluid shear stress (FSS) is crucial for vascular homeostasis, coordinating endothelial cell (EC) behavior and endothelial-mural cell communication.
- Disrupted flow sensing and excessive EC proliferation contribute to arterial-venous malformations (AVMs) in Hereditary Hemorrhagic Telangiectasia (HHT).
- The study used in vitro shear stress assays and in vivo analyses of murine HHT models, including endothelial-specific loss of Alk1 or Smad4 and BMP9/10 ligand blockade.
- AVM endothelium showed excessive flow-induced KLF4-Akt pathway activation, sustained EC proliferation, and loss of FSS-mediated CDK2/6 inhibition.
- Hyperproliferation suppressed PDGFB expression, leading to pericyte loss and mural cell remodeling in AVMs.
- Restoration of endothelial quiescence via KLF4, Akt, or CDK4/6 inhibition rescued FSS-induced PDGFB expression.
- Thalidomide-induced PDGFB upregulation restored mural cell coverage and reduced AVM burden in vivo.
- The study identifies EC cycle state as the upstream determinant of mural cell stability under pathological flow.