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Most prior work has treated BMP (bone morphogenetic protein) component depletion as mechanistically interchangeable, yet whether distinct genes converge on a shared mechanism remains unclear. We aimed to understand the molecular relationship between BMP signaling and endothelial flow response that leads to arteriovenous malformation formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We expose human endothelial monolayers treated with small interfering RNA against\n                      <jats:italic toggle=\"yes\">SMAD4<\/jats:italic>\n                      or\n                      <jats:italic toggle=\"yes\">ALK1<\/jats:italic>\n                      to laminar flow and analyze flow-responsive transcriptomics, flow-responsive BMP signaling activation dynamics, cell polarity, and morphology. We analyze the cell-autonomous and noncell-autonomous migration dynamics of endothelial cells treated with\n                      <jats:italic toggle=\"yes\">siSMAD4<\/jats:italic>\n                      or\n                      <jats:italic toggle=\"yes\">siALK1<\/jats:italic>\n                      . Using the postnatal mouse retina model, we study endothelial cell distribution changes over time in mosaic settings, and assess the remodeling capabilities of\n                      <jats:italic toggle=\"yes\">Smad4<\/jats:italic>\n                      <jats:sup>iECKO<\/jats:sup>\n                      or\n                      <jats:italic toggle=\"yes\">Alk1<\/jats:italic>\n                      <jats:sup>iECKO<\/jats:sup>\n                      , relative to littermate controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      This study shows that depletion of\n                      <jats:italic toggle=\"yes\">SMAD4<\/jats:italic>\n                      or\n                      <jats:italic toggle=\"yes\">ALK1<\/jats:italic>\n                      leads to fundamentally distinct mechanisms of vascular malformation.\n                      <jats:italic toggle=\"yes\">SMAD4<\/jats:italic>\n                      deficiency enhances endothelial responses to blood flow, including transcriptional activation and migration against flow, causing excessive capillary pruning and the development of single large shunts. In contrast,\n                      <jats:italic toggle=\"yes\">ALK1<\/jats:italic>\n                      deficiency disrupts flow sensing, impairs cell polarization and migration, and promotes a persistent angiogenic state, resulting in dense, hypervascularized networks. RNA sequencing across static and flow conditions identifies both flow-dependent and flow-independent transcriptional changes, suggesting early defects in endothelial fate specification. Mosaic in vitro models show that mutant cells co-opt neighboring wild-type cells, while in vivo tracking confirms mutation-specific migration behavior.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>These findings reveal divergent cellular programs driving arteriovenous malformations and underscore the need for gene-specific diagnostic and therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.125.323908","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T09:00:16Z","timestamp":1784192416000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Gene-Specific Endothelial Programs Drive AVM Pathogenesis in\n                    <i>SMAD4<\/i>\n                    and\n                    <i>ALK1<\/i>\n                    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