THU0351 LOW ER? EXPRESSION MIGHT BE IMPLICATED IN THE DEVELOPMENT OF PULMONARY HYPERTENSION IN FEMALE MICE LACKING PSGL-1
Authors: Rafael Gonzlez-Tajuelo, Mara De la Fuente-Fernndez, Daniel Morales-Cano, Antonio Muoz-Callejas, Juan Manuel Serrador, Bianca Barreira, Javier Silvn, Carlos Gamallo, Esther Vicente, Santos Castaeda, Francisco Prez-Vizcano, Angel Cogolludo, Ana Urzainqui
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Pulmonary arterial hypertension (PAH) is a rare disease with unknown etiopathogenesis and no curative treatment [1]. PAH is one of the major complications of connective tissue diseases, and 7-15% of patients with systemic sclerosis (SSc) develop PAH [2]. Mice deficient for the leukocytic receptor P-selectin glycoprotein ligand-1 (<i>PSGL-1<sup>-/-</sup></i>) spontaneously develop a SSc-like autoimmune syndrome with ageing [3]. <h3>Objectives</h3> To check whether <i>PSGL1<sup>-/-</sup></i> mice may develop PAH and the molecular mechanisms that might be implicated in the initiation and establishment of the disease. <h3>Methods</h3> Doppler pulse echochardiography was used to evaluate pulmonary artery flow acceleration time/ejection time (PAAT/ET) ratio in WT and <i>PSGL-1<sup>-/-</sup></i> C57BL/6 mice. Isolated pulmonary artery rings were incubated with acetylcholine and responses were registered with a wire myograph coupled to an isometric force transducer. Expression levels of the NO-sensing probe DAR-4M AM by fluorescence microscopy and flow cytometry. Angiotensin II lung concentration was quantified by ELISA. eNOS, p-ENOS, AT1R and AT2R expression was evaluated by western blot. In all cases, data are expressed as the meanSD. <h3>Results</h3> Aged <i>PSGL-1<sup>-/-</sup></i> females showed reduced flow PAAT/ET ratio indicating PAH. Moreover, pulmonary arterial rings from aged <i>PSGL-1<sup>-/-</sup></i> females presented ROS-independent reduced vasodilation response to acetylcholine. Importantly, eNOS phosphorylation was impaired and NO production by lung EC was reduced in aged <i>PSGL-1<sup>-/-</sup></i> females. Vascular remodeling and reduced expression of AT2R were observed in lungs of <i>PSGL-1<sup>-/-</sup></i> females from a younger age. With ageing, the levels of angiotensin II and the percentages of IFN?-producing interstitial macrophages, T and B lymphocytes were increased in <i>PSGL-1<sup>-/-</sup></i> females. The differences in the gender-biased genotype could be explained by the reduced expression of ERa in the lungs of aged <i>PSGL-1<sup>-/-</sup></i> females while WT and <i>PSGL-1<sup>-/-</sup></i> males showed similar expression. <h3>Conclusion</h3> PSGL-1 deficiency leads to pulmonary hypertension in &gt;18-months-old female mice, involving various mechanisms: Lung vessel wall remodeling and reduced AT2R expression. Reduced eNOS phosphorylation and reduced NO production with the subsequent specific lung endothelial dysfunction in PSGL-1<sup>-/-</sup> females. Importantly, ROS production is not increased nor help to NO reduction. Increased pulmonary AngII levels with ageing in PSGL-1<sup>-/-</sup> females. Increased Th1 polarization, reduced Treg population and increased IFN-? production by interstitial macrophages. Impaired ageing up-regulation of ERa expression in the lungs of PSGL-1<sup>-/-</sup> females. <h3>References</h3> [1] Montani et al. Orphanet Journal of Rare Diseases. 2013, 8 (97). [2] Tedford et al. Circ Heart Fail. 2013, 6 (5): 953-63. [3] Prez-Fras et al. Arthritis Rheumatol. 2014, 66 (11): 3178-89. <h3>Disclosure of Interests</h3> Rafael Gonzlez-Tajuelo: None declared, Mara De la Fuente-Fernndez: None declared, Daniel Morales-Cano: None declared, Antonio Muoz-Callejas: None declared, Juan Manuel Serrador: None declared, Bianca Barreira: None declared, Javier Silvn: None declared, Carlos Gamallo: None declared, Esther Vicente: None declared, Santos Castaeda Consultant for: Amgen, BMS, Pfizer, Lilly, MSD, Roche, Sanofi, UCB, Francisco Prez-Vizcano: None declared, Angel Cogolludo: None declared, Ana Urzainqui: None declared