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Here, we report a role for NKX2-5 in vascular smooth muscle cell phenotypic modulation in vitro and in vascular remodeling in vivo. NKX2-5 is upregulated in scleroderma patients with pulmonary arterial hypertension. Suppression of NKX2-5 expression in smooth muscle cells halted vascular smooth muscle proliferation and migration, enhanced contractility, and blocked the expression of extracellular matrix genes. Conversely, overexpression of NKX2-5 suppressed the expression of contractile genes (\n                    <jats:italic>ACTA2<\/jats:italic>\n                    ,\n                    <jats:italic>TAGLN<\/jats:italic>\n                    ,\n                    <jats:italic>CNN1<\/jats:italic>\n                    ) and enhanced the expression of matrix genes (\n                    <jats:italic>COL1<\/jats:italic>\n                    ) in vascular smooth muscle cells. In vivo, conditional deletion of NKX2-5 attenuated blood vessel remodeling and halted the progression to hypertension in a mouse chronic hypoxia model. This study revealed that signals related to injury such as serum and low confluence, which induce NKX2-5 expression in cultured cells, is potentiated by TGF-\u03b2 and further enhanced by hypoxia. The effect of TGF-\u03b2 was sensitive to ERK5 and PI3K inhibition. Our data suggest a pivotal role for NKX2-5 in the phenotypic modulation of smooth muscle cells during pathological vascular remodeling and provide proof of concept for therapeutic targeting of NKX2-5 in vasculopathies.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.164191","type":"journal-article","created":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T14:00:31Z","timestamp":1716300031000},"source":"Crossref","is-referenced-by-count":4,"title":["NKX2-5 regulates vessel remodeling in scleroderma-associated pulmonary arterial hypertension"],"prefix":"10.1172","volume":"9","author":[{"given":"Ioannis","family":"Papaioannou","sequence":"first","affiliation":[{"name":"Division of Medicine, Department of Inflammation, University College London, Royal Free Campus, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athina","family":"Dritsoula","sequence":"additional","affiliation":[{"name":"Division of Medicine, Department of 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