Loss and gain of function studies were employed to define disease mechanisms.<h4>Results</h4>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 gene discussed is AKT1; the disease is telangiectasia, hereditary hemorrhagic, type 2.