title: Suppression of endothelial CD39/ENTPD1 is associated with pulmonary vascular remodeling in pulmonary arterial hypertension.
abstract: Endothelial cell (EC) dysfunction plays a role in the pathobiology of occlusive vasculopathy in pulmonary arterial hypertension (PAH). Purinergic signaling pathways, which consist of extracellular nucleotide and nucleoside-mediated cell signaling through specific receptors, are known to be important regulators of vascular tone and remodeling. Therefore, we hypothesized that abnormalities in the vascular purinergic microenvironment are associated with PAH. Enzymatic clearance is crucial to terminate unnecessary cell activation; one of the most abundantly expressed enzymes on the EC surface is E-NTPDase1/CD39, which hydrolyzes ATP and ADP to AMP. we used histological samples from patients and healthy donors, radioisotope-labeled substrates to measure ectoenzyme activity, and a variety of in vitro approaches to study the role of CD39 in PAH. Immunohistochemistry on human idiopathic PAH (IPAH) patients' lungs demonstrated that CD39 was significantly downregulated in the endothelium of diseased small arteries. Similarly, CD39 expression and activity were decreased in cultured pulmonary ECs from IPAH patients. Suppression of CD39 in vitro resulted in EC phenotypic switch that gave rise to apoptosis-resistant pulmonary arterial endothelial cells and promoted a microenvironment that induced vascular smooth muscle cell migration. we also identified that the ATP receptor P2Y11 is essential for ATP-mediated EC survival. Furthermore, we report that apelin, a known regulator of pulmonary vascular homeostasis, can potentiate the activity of CD39 both in vitro and in vivo. we conclude that sustained attenuation of CD39 activity through ATP accumulation is tightly linked to vascular dysfunction and remodeling in PAH and could represent a novel target for therapy.
authors.affiliation: Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland;
authors.forename: Mikko H
authors.initials: MH
authors.lastname: Helenius
authors.affiliation: Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland;
authors.forename: Sanna
authors.initials: S
authors.lastname: Vattulainen
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California;
authors.forename: Mark
authors.initials: M
authors.lastname: Orcholski
authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland;
authors.forename: Joonas
authors.initials: J
authors.lastname: Aho
authors.affiliation: Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland;
authors.forename: Anne
authors.initials: A
authors.lastname: Komulainen
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland; and.
authors.forename: Pekka
authors.initials: P
authors.lastname: Taimen
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California;
authors.forename: Lingli
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California;
authors.forename: Vinicio A
authors.initials: VA
authors.lastname: de Jesus Perez
authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Juha W
authors.initials: JW
authors.lastname: Koskenvuo
authors.affiliation: Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; tero-pekka.alastalo@helsinki.fi.
authors.forename: Tero-Pekka
authors.initials: TP
authors.lastname: Alastalo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis*; D000073861:Apelin; D001081:Apyrase / Q000096:biosynthesis*; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011651:Pulmonary Artery / Q000201:enzymology* / Q000473:pathology; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: C115436:APLN protein, human; D015703:Antigens, CD; D000073861:Apelin; D036341:Intercellular Signaling Peptides and Proteins; C109734:P2RY11 protein, human; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen
keywords: ATP; NTPDaseI/CD39; apelin; pulmonary arterial hypertension; vascular remodeling