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      Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

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          Abstract

          Objective

          Pulmonary arterial hypertension (PAH), one of the major complications of systemic sclerosis (SSc), is a rare disease with unknown etiopathogenesis and noncurative treatments. As mice deficient in P‐selectin glycoprotein ligand 1 (PSGL‐1) develop a spontaneous SSc‐like syndrome, we undertook this study to analyze whether they develop PAH and to examine the molecular mechanisms involved.

          Methods

          Doppler echocardiography was used to estimate pulmonary pressure, immunohistochemistry was used to assess vascular remodeling, and myography of dissected pulmonary artery rings was used to analyze vascular reactivity. Angiotensin II (Ang II) levels were quantified by enzyme‐linked immunosorbent assay, and Western blotting was used to measure Ang II type 1 receptor (AT 1R), AT 2R, endothelial cell nitric oxide synthase (eNOS), and phosphorylated eNOS expression in lung lysates. Flow cytometry allowed us to determine cytokine production by immune cells and NO production by endothelial cells. In all cases, there were 4–8 mice per experimental group.

          Results

          PSGL‐1 −/− mice showed lung vessel wall remodeling and a reduced mean ± SD expression of pulmonary AT 2R (expression ratio [relative to β‐actin] in female mice age >18 months: wild‐type mice 0.799 ± 0.508 versus knockout mice 0.346 ± 0.229). With aging, female PSGL‐1 −/− mice had impaired up‐regulation of estrogen receptor α (ERα) and developed lung vascular endothelial dysfunction coinciding with an increase in mean ± SEM pulmonary Ang II levels (wild‐type 48.70 ± 5.13 pg/gm lung tissue versus knockout 78.02 ± 28.09 pg/gm lung tissue) and a decrease in eNOS phosphorylation, leading to reduced endothelial NO production. These events led to a reduction in the pulmonary artery acceleration time:ejection time ratio in 33% of aged female PSGL‐1 −/− mice, indicating pulmonary hypertension. Importantly, we found expanded populations of interferon‐γ–producing PSGL‐1 −/− T cells and B cells and a reduced presence of regulatory T cells.

          Conclusion

          The absence of PSGL‐1 induces a reduction in Treg cells, NO production, and ERα expression and causes an increase in Ang II in the lungs of female mice, favoring the development of PAH.

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          Most cited references 45

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          Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure.

          At present, six groups of chronic pulmonary hypertension (PH) are described. Among these, group 1 (and 1') comprises a group of diverse diseases termed pulmonary arterial hypertension (PAH) that have several pathophysiological, histological, and prognostic features in common. PAH is a particularly severe and progressive form of PH that frequently leads to right heart failure and premature death. The diagnosis of PAH must include a series of defined clinical parameters, which extend beyond mere elevations in pulmonary arterial pressures and include precapillary PH, pulmonary hypertensive arteriopathy (usually with plexiform lesions), slow clinical onset (months or years), and a chronic time course (years) characterized by progressive deterioration. What appears to distinguish PAH from other forms of PH is the severity of the arteriopathy observed, the defining characteristic of which is "plexogenic arteriopathy." The pathogenesis of this arteriopathy remains unclear despite intense investigation in a variety of animal model systems. The most commonly used animal models ("classic" models) are rodents exposed to either hypoxia or monocrotaline. Newer models, which involve modification of classic approaches, have been developed that exhibit more severe PH and vascular lesions, which include neointimal proliferation and occlusion of small vessels. In addition, genetically manipulated mice have been generated that have provided insight into the role of specific molecules in the pulmonary hypertensive process. Unfortunately, at present, there is no perfect preclinical model that completely recapitulates human PAH. All models, however, have provided and will continue to provide invaluable insight into the numerous pathways that contribute to the development and maintenance of PH. Use of both classic and newly developed animal models will allow continued rigorous testing of new hypotheses regarding pathogenesis and treatment. This review highlights progress that has been made in animal modeling of this important human condition.
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            Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase.

            Oestrogen produces diverse biological effects through binding to the oestrogen receptor (ER). The ER is a steroid hormone nuclear receptor, which, when bound to oestrogen, modulates the transcriptional activity of target genes. Controversy exists, however, concerning whether ER has a role outside the nucleus, particularly in mediating the cardiovascular protective effects of oestrogen. Here we show that the ER isoform, ER alpha, binds in a ligand-dependent manner to the p85alpha regulatory subunit of phosphatidylinositol-3-OH kinase (PI(3)K). Stimulation with oestrogen increases ER alpha-associated PI(3)K activity, leading to the activation of protein kinase B/Akt and endothelial nitric oxide synthase (eNOS). Recruitment and activation of PI(3)K by ligand-bound ER alpha are independent of gene transcription, do not involve phosphotyrosine adapter molecules or src-homology domains of p85alpha, and extend to other steroid hormone receptors. Mice treated with oestrogen show increased eNOS activity and decreased vascular leukocyte accumulation after ischaemia and reperfusion injury. This vascular protective effect of oestrogen was abolished in the presence of PI(3)K or eNOS inhibitors. Our findings define a physiologically important non-nuclear oestrogen-signalling pathway involving the direct interaction of ER alpha with PI(3)K.
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              Vascular nitric oxide: Beyond eNOS.

              As the first discovered gaseous signaling molecule, nitric oxide (NO) affects a number of cellular processes, including those involving vascular cells. This brief review summarizes the contribution of NO to the regulation of vascular tone and its sources in the blood vessel wall. NO regulates the degree of contraction of vascular smooth muscle cells mainly by stimulating soluble guanylyl cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP), although cGMP-independent signaling [S-nitrosylation of target proteins, activation of sarco/endoplasmic reticulum calcium ATPase (SERCA) or production of cyclic inosine monophosphate (cIMP)] also can be involved. In the blood vessel wall, NO is produced mainly from l-arginine by the enzyme endothelial nitric oxide synthase (eNOS) but it can also be released non-enzymatically from S-nitrosothiols or from nitrate/nitrite. Dysfunction in the production and/or the bioavailability of NO characterizes endothelial dysfunction, which is associated with cardiovascular diseases such as hypertension and atherosclerosis.
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                Author and article information

                Contributors
                ana.urzainqui@salud.madrid.org
                Journal
                Arthritis Rheumatol
                10.1002/(ISSN)2326-5205
                ART
                Arthritis & Rheumatology (Hoboken, N.j.)
                John Wiley and Sons Inc. (Hoboken )
                2326-5191
                2326-5205
                28 January 2020
                March 2020
                : 72
                : 3 ( doiID: 10.1002/art.v72.3 )
                : 477-487
                Affiliations
                [ 1 ] Fundación de Investigación Biomédica‐Hospital de la Princesa IIS‐Princesa, Servicio de Inmunlogía Madrid Spain
                [ 2 ] University Complutense of Madrid School of Medicine and Ciber Enfermedades Respiratorias Madrid Spain
                [ 3 ] Centro de Biología Molecular Severo Ochoa (CBMSO) and Instituto de Física Teórica CSIC/Universidad Autónoma de Madrid (UAM) Madrid Spain
                [ 4 ] Fundación de Investigación Biomédica‐Hospital de la Princesa IIS‐Princesa, and CBMSO, CSIC‐UAM Madrid Spain
                [ 5 ] Fundación de Investigación Biomédica‐Hospital de la Princesa IIS‐Princesa, and Catedra UAM‐ROCHE Madrid Spain
                [ 6 ] Hospital de la Princesa and Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid Spain
                Author notes
                [* ]Address correspondence to Ana Urzainqui, PhD, Hospital de la Princesa, Calle de Diego de León 62, 28006 Madrid, Spain. E‐mail: ana.urzainqui@ 123456salud.madrid.org .
                Article
                ART41100
                10.1002/art.41100
                7065124
                31509349
                © 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 6, Tables: 0, Pages: 11, Words: 7864
                Product
                Funding
                Funded by: Spanish Ministry of Health and Instituto de Salud Carlos III (ISCIII) (cofinanced by Fondos FEDER)
                Award ID: AC17‐00027
                Funded by: Spanish Ministry of Economy and Competitiveness
                Award ID: SAF2015‐69396‐R, SAF2011‐28150, SAF 2014‐55399
                Funded by: Spanish Ministry of Health and Instituto de Salud Carlos III (ISCIII) (cofinanced by Fondos FEDER)
                Award ID: FIS‐PI14‐01698, FIS‐PI17‐ 01819, FIS‐PI12‐01578
                Categories
                Original Article
                Systemic Sclerosis
                Custom metadata
                2.0
                March 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.7 mode:remove_FC converted:11.03.2020

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