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Patients with ACDC develop vessel arteriomegaly, tortuosity, and vascular calcification in their lower extremity arteries. Histological analysis shows that patients with ACDC vessels exhibit fragmented elastin fibers similar to that seen in aneurysmal-like pathologies. It is known that alterations in transforming growth factor \u03b2 (TGF\u03b2) pathway signaling contribute to this elastin phenotype in several connective tissue diseases, as TGF\u03b2 regulates extracellular matrix (ECM) remodeling. Our study investigates whether CD73-derived adenosine modifies TGF\u03b2 signaling in vascular smooth muscle cells (SMCs). We show that Nt5e<jats:sup>\u2212\/\u2212<\/jats:sup> SMCs have elevated contractile markers and elastin gene expression compared with Nt5e<jats:sup>+\/+<\/jats:sup> SMCs. Ecto-5\u2032-nucleotidase ( Nt5e)-deficient SMCs exhibit increased TGF\u03b2-2 and activation of small mothers against decapentaplegic (SMAD) signaling, elevated elastin transcript and protein, and potentiate SMC contraction. These effects were diminished when the A2b adenosine receptor was activated. Our results identify a novel link between adenosine and TGF\u03b2 signaling, where adenosine signaling via the A2b adenosine receptor attenuates TGF\u03b2 signaling to regulate SMC homeostasis. We discuss how disruption in adenosine signaling is implicated in ACDC vessel tortuosity and could potentially contribute to other aneurysmal pathogenesis. <\/jats:p>","DOI":"10.1152\/ajpcell.00054.2022","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T13:43:31Z","timestamp":1670852611000},"page":"C327-C338","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Ecto-5\u2032-nucleotidase (Nt5e\/CD73)-mediated adenosine signaling attenuates TGF\u03b2-2 induced elastin and cellular contraction"],"prefix":"10.1152","volume":"324","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3571-5845","authenticated-orcid":false,"given":"Rolando A.","family":"Cuevas","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania"},{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of 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