title: Endothelial actions of atrial natriuretic peptide prevent pulmonary hypertension in mice.
abstract: The cardiac hormone atrial natriuretic peptide (ANP) regulates systemic and pulmonary arterial blood pressure by activation of its cyclic GMP-producing guanylyl cyclase-A (GC-A) receptor. In the lung, these hypotensive effects were mainly attributed to smooth muscle-mediated vasodilatation. It is unknown whether pulmonary endothelial cells participate in the homeostatic actions of ANP. Therefore, we analyzed GC-A/cGMP signalling in lung endothelial cells and the cause and functional impact of lung endothelial GC-A dysfunction. Western blot and cGMP determinations showed that cultured human and murine pulmonary endothelial cells exhibit prominent GC-A expression and activity which were markedly blunted by hypoxia, a condition known to trigger pulmonary hypertension (PH). To elucidate the consequences of impaired endothelial ANP signalling, we studied mice with genetic endothelial cell-restricted ablation of the GC-A receptor (EC GC-A KO). Notably, EC GC-A KO mice exhibit PH already under resting, normoxic conditions, with enhanced muscularization of small arteries and perivascular infiltration of inflammatory cells. These alterations were aggravated on exposure of mice to chronic hypoxia. Lung endothelial GC-A dysfunction was associated with enhanced expression of angiotensin converting enzyme (ACE) and increased pulmonary levels of Angiotensin II. Angiotensin II/AT1-blockade with losartan reversed pulmonary vascular remodelling and perivascular inflammation of EC GC-A KO mice, and prevented their increment by chronic hypoxia. This experimental study indicates that endothelial effects of ANP are critical to prevent pulmonary vascular remodelling and PH. Chronic endothelial ANP/GC-A dysfunction, e.g. provoked by hypoxia, is associated with activation of the ACE-angiotensin pathway in the lung and PH.
authors.affiliation: Physiologisches Institut der Universität Würzburg, Röntgenring 9, 97070, Würzburg, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Werner
authors.affiliation: Department of Internal Medicine, University of Gießen and Marburg Lung Center (UGMLC), Justus-Liebig University Gießen, Giessen, Germany.|German Center for Lung Research, Heidelberg, Germany.
authors.forename: Baktybek
authors.initials: B
authors.lastname: Kojonazarov
authors.affiliation: Physiologisches Institut der Universität Würzburg, Röntgenring 9, 97070, Würzburg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Gaßner
authors.affiliation: Physiologisches Institut der Universität Würzburg, Röntgenring 9, 97070, Würzburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Abeßer
authors.affiliation: Physiologisches Institut der Universität Würzburg, Röntgenring 9, 97070, Würzburg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Schuh
authors.affiliation: Physiologisches Institut der Universität Würzburg, Röntgenring 9, 97070, Würzburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Völker
authors.affiliation: Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.affiliation: Department of Internal Medicine, University of Gießen and Marburg Lung Center (UGMLC), Justus-Liebig University Gießen, Giessen, Germany.|German Center for Lung Research, Heidelberg, Germany.
authors.forename: Bhola K
authors.initials: BK
authors.lastname: Dahal
authors.affiliation: Department of Internal Medicine, University of Gießen and Marburg Lung Center (UGMLC), Justus-Liebig University Gießen, Giessen, Germany.|German Center for Lung Research, Heidelberg, Germany.
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.affiliation: Physiologisches Institut der Universität Würzburg, Röntgenring 9, 97070, Würzburg, Germany. michaela.kuhn@mail.uni-wuerzburg.de.
authors.forename: Michaela
authors.identifier: http://orcid.org/0000-0002-9812-5906
authors.initials: M
authors.lastname: Kuhn
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000209:etiology; D000860:Hypoxia / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D007703:Peptidyl-Dipeptidase A; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A
keywords: Atrial natriuretic peptide; Cyclic GMP; Endothelium; Guanylyl cyclase-A; Pulmonary hypertension