{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:13:12Z","timestamp":1791144792270,"version":"4.1.0"},"reference-count":67,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T00:00:00Z","timestamp":1731888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["22K07843"],"award-info":[{"award-number":["22K07843"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["18K07841"],"award-info":[{"award-number":["18K07841"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["20K08565"],"award-info":[{"award-number":["20K08565"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["18K08192"],"award-info":[{"award-number":["18K08192"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["17K11075"],"award-info":[{"award-number":["17K11075"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["19K07318"],"award-info":[{"award-number":["19K07318"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Contracted Research Grants from Janssen Pharmaceutical K.K","award":["CRG2022"],"award-info":[{"award-number":["CRG2022"]}]},{"name":"Contracted Research Grants from Janssen Pharmaceutical K.K","award":["AJPS20210713002"],"award-info":[{"award-number":["AJPS20210713002"]}]},{"name":"Contracted Research Grants from Janssen Pharmaceutical K.K","award":["CRG2023:18_2022071404"],"award-info":[{"award-number":["CRG2023:18_2022071404"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>We investigated whether the disruption of C\u2013C motif chemokine receptor (CCR) 2 may attenuate the development of pulmonary arterial hypertension (PAH) in any rat models with the reversal of the associated pro-inflammatory state and vascular dysfunction, and synergize with a conventional pulmonary vasodilator.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Using Ccr2(\u2212\/\u2212) rats generated by CRISPR\/Cas9, we investigated pulmonary hypertension (PH) in Ccr2(+\/+) or Ccr2(\u2212\/\u2212) rats treated with monocrotaline (MCT), SU5416\/hypoxia (SuHx) and chronic hypoxia (CH). Ccr2(\u2212\/\u2212) decreased the right ventricular systolic pressure, an index of right ventricular hypertrophy and mortality rate, and reversed increased expression of inflammatory cytokines\/chemokines [interleukin-6, tumour necrosis factor-\u03b1, C\u2013C motif chemokine receptor (CCL)-2, interleukin-1\u03b2, transforming growth factor-\u03b2] in rats 3weeks after MCT injection, but not in SuHx or CH models. Consistently, Ccr2(\u2212\/\u2212) decreased indices of pulmonary vascular diseases (PVDs) and perivascular macrophage infiltration, as well as reversed impaired bone morphogenetic protein receptor type 2 signalling, increased endothelial apoptosis and impaired nitric oxide signalling and decreased phosphodiesterase-5 (PDE5) expression in lungs in MCT-treated rats. Gene expression of receptors for prostaglandin I2 and endothelin was not changed by Ccr2(\u2212\/\u2212) in MCT-treated rats. In cultured pulmonary arterial smooth muscle cells (PASMCs), Ccr2(\u2212\/\u2212) suppressed CCL2-induced hyperproliferation and dedifferentiation as well as reversed CCL2-induced decrease in PDE5 expression. The whole-genome RNA sequencing analysis identified differentially expressed genes in CCL2-stimulated Ccr2(\u2212\/\u2212) PASMCs, which are related to the regulation of cellular differentiation and contraction. Based on studies in rats and cultured PASMCs, we investigated whether a PDE5 inhibitor, tadalafil, synergizes with Ccr2(\u2212\/\u2212). Tadalafil administration ameliorated PH and PVDs in MCT-treated Ccr2(\u2212\/\u2212) rats but not in Ccr2(+\/+) rats. Tadalafil further improved survival in MCT-treated Ccr2(\u2212\/\u2212) rats.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The present findings demonstrated that CCR2 disruption ameliorated PAH in MCT-treated rats, which was associated with the reversal of dysregulated inflammatory pathways and vascular dysfunction and synergized with tadalafil. These findings suggest that CCR2 may be a therapeutic target in intractable PAH patients with a certain CCR2-related inflammatory phenotype and refractory to conventional pulmonary vasodilators.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvae244","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T15:31:41Z","timestamp":1731943901000},"page":"1076-1090","source":"Crossref","is-referenced-by-count":15,"title":["C\u2013C Motif chemokine receptor-2 blockade ameliorates pulmonary hypertension in rats and synergizes with a pulmonary vasodilator"],"prefix":"10.1093","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8190-3874","authenticated-orcid":false,"given":"Naoki","family":"Tsuboya","sequence":"first","affiliation":[{"name":"The Department of Pediatrics, Mie University Graduate School of Medicine , Mie 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