{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:29:15Z","timestamp":1768516155581,"version":"3.49.0"},"posted":{"date-parts":[[2024,11,28]]},"group-title":"Pathology","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T00:00:00Z","timestamp":1732752000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,12,4]]},"abstract":"<jats:p>\n                  Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder with manifestations including severe nose bleeding and microhemorrhage in brains. Despite being the second most common inherited bleeding disorder, the pathophysiological mechanism underlying HHT-associated hemorrhage is poorly understood. HHT pathogenesis is thought to follow a Knudsonian two-hit model, requiring a second somatic mutation for lesion formation. Mutations in activin receptor-like kinase 1 (\n                  <jats:italic>ALK1<\/jats:italic>\n                  ) gene cause HHT type 2. We hypothesize that somatic mutation of\n                  <jats:italic>Alk1<\/jats:italic>\n                  in arterial endothelial cells (AECs) leads to arterial defects and hemorrhage. Here, we mutated\n                  <jats:italic>Alk1<\/jats:italic>\n                  in AECs in postnatal mice using\n                  <jats:italic>\n                    Bmx(PAC)-Cre\n                    <jats:sup>ERT2<\/jats:sup>\n                  <\/jats:italic>\n                  and found that somatic arterial endothelial mutation of\n                  <jats:italic>Alk1<\/jats:italic>\n                  was sufficient to induce spontaneous epistaxis and multifocal cerebral microhemorrhage. This bleeding occurred in the presence of tortuous and enlarged blood vessels, loss of arterial molecular marker\n                  <jats:italic>Efnb2<\/jats:italic>\n                  , disorganization of vascular smooth muscle, and impaired vasoregulation. Our data suggest that arterial endothelial deletion of\n                  <jats:italic>Alk1<\/jats:italic>\n                  leading to reduced arterial identity and disrupted vascular smooth muscle cell coverage is a plausible molecular mechanism for HHT-associated severe epistaxis. This work provides the first evidence that somatic\n                  <jats:italic>Alk1<\/jats:italic>\n                  mutation in AECs can cause hemorrhagic vascular lesions, offering a novel preclinical model critically needed for studying HHT-associated epistaxis, and delineating an arterial mechanism to HHT pathophysiology.\n                <\/jats:p>","DOI":"10.1101\/2024.11.25.622742","type":"posted-content","created":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T05:00:50Z","timestamp":1732770050000},"source":"Crossref","is-referenced-by-count":0,"title":["Arterial endothelial deletion of hereditary hemorrhagic telangiectasia 2\/\n                  <i>Alk1<\/i>\n                  causes epistaxis and cerebral microhemorrhage with aberrant arteries and defective smooth muscle coverage"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2930-1176","authenticated-orcid":false,"given":"Xuetao","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4411-7855","authenticated-orcid":false,"given":"Kyle A","family":"Jacobs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5517-7706","authenticated-orcid":false,"given":"Kunal P","family":"Raygor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0463-257X","authenticated-orcid":false,"given":"Shang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8413-9697","authenticated-orcid":false,"given":"Jiajun","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7882-2475","authenticated-orcid":false,"given":"Rong A","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024120611104416000_2024.11.25.622742v2.1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P"},{"key":"2024120611104416000_2024.11.25.622742v2.2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI176379"},{"key":"2024120611104416000_2024.11.25.622742v2.3","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320320302"},{"key":"2024120611104416000_2024.11.25.622742v2.4","doi-asserted-by":"crossref","unstructured":"Kasthuri RS , Montifar M , Nelson J , Kim H , Lawton MT , Faughnan ME , the Brain Vascular Malformation Consortium HHT Investigator Group. Prevalence and predictors of anemia in hereditary hemorrhagic telangiectasia. Am J Hematol [Internet]. 2017 [cited 2024 Oct 6];92. 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