Divergent endothelial mechanisms drive arteriovenous malformations in Alk1 and SMAD4 loss-of-function.

ABSTRACT: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder caused by mutations in the bone morphogenetic protein signaling pathway, leading to arteriovenous malformations. While previously thought to share molecular and cellular dysregulation, this study reveals highly distinct mechanisms depending on whether mutations occur in Alk1 or SMAD4. Loss of SMAD4 enhances endothelial cell responses to flow, including flow-regulated transcription and cell migration against blood flow, causing excessive pruning of capillaries and the formation of single large shunts. Conversely, Alk1 deficiency disrupts endothelial flow responses, including cell polarization and directional migration, leading to a dense vascular network and the persistence of a malformation nidus. In vivo cell populati

SUBMITTER: Oppenheim O 

PROVIDER: S-EPMC11741317 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature