{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:02:08Z","timestamp":1785438128454,"version":"3.56.0"},"posted":{"date-parts":[[2025,1,3]]},"group-title":"Developmental Biology","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T00:00:00Z","timestamp":1735862400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["TNE ATTRACT 17CVD03"],"award-info":[{"award-number":["TNE ATTRACT 17CVD03"]}],"id":[{"id":"https:\/\/ror.org\/01czwga19","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Hereditary hemorrhagic telangiectasia is a genetic disorder caused by loss-of-function mutations in components of the bone morphogenetic protein signaling pathway, leading to arteriovenous malformations. Most prior work has treated BMP-component mutations 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 AVM 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 siRNA against SMAD4 or ALK1 to laminar flow and analyze flow-responsive transcriptomics, flow-responsive BMP signaling activation dynamics, cell polarity and morphology. We analyze the cell-autonomous and non-cell-autonomous migration dynamics of ECs treated with siSMAD4 or siALK1. Using the postnatal mouse retina model, we study EC distribution changes over time in mosaic settings, and assess the remodelling capabilities of Smad4\n                    <jats:sup>iECKO<\/jats:sup>\n                    or Alk1\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>This study shows that mutations in SMAD4 or ALK1 lead to fundamentally distinct mechanisms of malformation formation. SMAD4 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, ALK1 deficiency disrupts flow sensing, impairs cell polarization and migration, and promotes a persistent angiogenic state, resulting in dense, hypervascularized networks. RNA sequencing reveals that these transcriptional changes precede flow onset, 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.<\/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>\n                <jats:sec>\n                  <jats:title>Clinical Perspective<\/jats:title>\n                  <jats:sec>\n                    <jats:title>What is New?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>This study identifies gene-specific mechanisms of AVM formation in endothelial cells with SMAD4 or ALK1 loss-of-function, two major mutations underlying Hereditary Hemorrhagic Telangiectasia.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Using multiple side-by-side analyses, the study reveals that SMAD4 deficiency enhances flow-mediated remodeling, while ALK1 deficiency impairs flow sensing and promotes angiogenic persistence.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>RNA sequencing showed that several transcriptional differences precede the onset of flow, indicating early divergence in endothelial cell fate specification and mechanosensory behavior.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Mosaic culture and retinal models demonstrate that mutant cells exert distinct non-cell-autonomous effects on wild-type endothelial cells.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>What Are the Clinical Implications?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>This work challenges the prevailing assumption of a unified pathogenic pathway in HHT and supports a model of mutation-specific AVM pathogenesis, with distinct cellular and molecular drivers.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>The findings provide a mechanistic basis for the variable clinical presentation seen in patients with different HHT mutations.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Identification of early transcriptional signatures, such as persistent ANGPT2 or DPP4 upregulation, may offer new biomarkers or therapeutic targets for early intervention before AVMs become clinically symptomatic.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Personalized therapeutic strategies could reduce reliance on invasive treatments and shift toward mechanism-based, precision medicine approaches in HHT and related vascular disorders.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.03.631070","type":"posted-content","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T15:40:26Z","timestamp":1736178026000},"source":"Crossref","is-referenced-by-count":5,"title":["Gene-specific endothelial programs drive AVM pathogenesis in SMAD4 and ALK1 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