{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:45:07Z","timestamp":1790675107930,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T00:00:00Z","timestamp":1580169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>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\u2010selectin glycoprotein ligand 1 (PSGL\u20101) develop a spontaneous SSc\u2010like syndrome, we undertook this study to analyze whether they develop PAH and to examine the molecular mechanisms involved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2010linked immunosorbent assay, and Western blotting was used to measure Ang II type 1 receptor (AT<jats:sub>1<\/jats:sub>R), AT<jats:sub>2<\/jats:sub>R, 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\u20138 mice per experimental group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PSGL\u20101<jats:sup>\u2212\/\u2212<\/jats:sup> mice showed lung vessel wall remodeling and a reduced mean \u00b1 SD expression of pulmonary AT<jats:sub>2<\/jats:sub>R (expression ratio [relative to \u03b2\u2010actin] in female mice age &gt;18 months: wild\u2010type mice 0.799 \u00b1 0.508 versus knockout mice 0.346 \u00b1 0.229). With aging, female PSGL\u20101<jats:sup>\u2212\/\u2212<\/jats:sup> mice had impaired up\u2010regulation of estrogen receptor \u03b1 (ER\u03b1) and developed lung vascular endothelial dysfunction coinciding with an increase in mean \u00b1 SEM pulmonary Ang II levels (wild\u2010type 48.70 \u00b1 5.13 pg\/gm lung tissue versus knockout 78.02 \u00b1 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\u20101<jats:sup>\u2212\/\u2212<\/jats:sup> mice, indicating pulmonary hypertension. Importantly, we found expanded populations of interferon\u2010\u03b3\u2013producing PSGL\u20101<jats:sup>\u2212\/\u2212<\/jats:sup> T cells and B cells and a reduced presence of regulatory T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The absence of PSGL\u20101 induces a reduction in Treg cells, NO production, and ER\u03b1 expression and causes an increase in Ang II in the lungs of female mice, favoring the development of PAH.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41100","type":"journal-article","created":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T08:42:52Z","timestamp":1568191372000},"page":"477-487","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P\u2010Selectin Glycoprotein Ligand 1\u2013Deficient Mice"],"prefix":"10.1002","volume":"72","author":[{"given":"Rafael","family":"Gonz\u00e1lez\u2010Tajuelo","sequence":"first","affiliation":[{"name":"Fundaci\u00f3n de Investigaci\u00f3n Biom\u00e9dica\u2010Hospital de la Princesa IIS\u2010Princesa, Servicio de Inmunlog\u00eda  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"de la Fuente\u2010Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n de Investigaci\u00f3n Biom\u00e9dica\u2010Hospital de la Princesa IIS\u2010Princesa, Servicio de Inmunlog\u00eda  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Morales\u2010Cano","sequence":"additional","affiliation":[{"name":"University Complutense of Madrid School of Medicine and Ciber Enfermedades Respiratorias  Madrid 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