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R01 HL169510"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:p>\n                    Vascular endothelial cells (ECs) encode a homeostatic fluid shear stress (FSS) set point that is essential for vascular stability. Deviations above or below this threshold trigger adaptive remodeling to restore physiological shear levels. Disruption of this control mechanism leads to enlarged arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia, a vascular disorder caused by heterozygous loss-of-function (LOF) mutation in\n                    <jats:italic>ALK1<\/jats:italic>\n                    ,\n                    <jats:italic>ENG<\/jats:italic>\n                    , or\n                    <jats:italic>SMAD4<\/jats:italic>\n                    . Mechanistically,\n                    <jats:italic>Smad4<\/jats:italic>\n                    -deficient ECs are reset to a lower FSS set point value, resulting in AVMs that show characteristics of high-FSS remodeling with elevated KLF4 and high activation of the downstream Akt. Here, we investigated the KLF4\/Akt upstream mechanisms by which SMAD4 sets the physiological FSS set point. We identified the receptor tyrosine kinase c-KIT as a component and regulator of the junctional mechanosensory receptor complex, which is highly upregulated in murine and human AVMs. SMAD4 restrains flow signaling by limiting c-KIT\u2013dependent ERK5 activation and\n                    <jats:italic>KLF4<\/jats:italic>\n                    induction. Thus,\n                    <jats:italic>SMAD4<\/jats:italic>\n                    LOF leads to sustained c-KIT engagement in the sensory junctional apparatus, driving enhanced and prolonged activation of the ERK5\/KLF4\/Akt signaling axis. These results show that\n                    <jats:italic>Smad4<\/jats:italic>\n                    -LOF mutations induce malformations by disabling a key homeostatic mechanism and identify c-KIT as a potentially previously unrecognized therapeutic target.\n                  <\/jats:p>","DOI":"10.1172\/jci197609","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:01:22Z","timestamp":1790791282000},"source":"Crossref","is-referenced-by-count":0,"title":["Loss of Smad4 drives vascular malformations via c-KIT\u2013dependent high\u2013fluid shear stress mimicry"],"prefix":"10.1172","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9066-0664","authenticated-orcid":true,"given":"Johannes","family":"Gahn","sequence":"first","affiliation":[{"name":"Experimental Pharmacology Mannheim (EPM) and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Wu","sequence":"additional","affiliation":[{"name":"Experimental 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