{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:27:07Z","timestamp":1791210427820,"version":"4.1.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2013,5,1]],"date-time":"2013-05-01T00:00:00Z","timestamp":1367366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In pulmonary arterial hypertension (PAH), there is overexpression of the chemokine, C-C chemokine ligand type 2 (CCL2), and infiltration of myeloid cells into the pulmonary vasculature. Inhibition of CCL2 in animals decreases PAH, suggesting that the CCL2 receptor (CCR2) plays a role in PAH development. To test this hypothesis, we exposed wild-type (WT) and CCR2-deficient (Ccr2\u2212\/\u2212) mice to chronic hypobaric hypoxia to induce PAH. After hypoxic stress, Ccr2\u2212\/\u2212 mice displayed a more severe PAH phenotype, as demonstrated by increased right ventricular (RV) systolic pressures, RV hypertrophy, and tachycardia relative to WT mice. However, these mice also exhibited increased RV systolic pressures and increased pulmonary artery muscularization under normoxic conditions. Moreover, Ccr2\u2212\/\u2212 mice displayed decreased pulmonary vascular branching at 3 weeks of age and increased vascular muscularization at birth, suggesting that an abnormality in pulmonary vascular development leads to spontaneous PAH in these animals. No significant differences in cytokine responses were observed between WT and Ccr2\u2212\/\u2212 mice during either normoxia or hypoxia. However, Ccr2\u2212\/\u2212 mice displayed increased Notch-3 signaling and dysregulated Notch ligand expression, suggesting a possible cause for their abnormal pulmonary vascular development. Our findings imply that CCR2 does not directly contribute to the development of PAH, but does play a previously unrecognized role in pulmonary vasculature development and remodeling wherein the absence of CCR2 results in spontaneous PAH, most likely via dysregulation of Notch signaling. Our results demonstrate that CCR2 has impacts beyond leukocyte recruitment, and is required for the proper expression of Notch signaling molecules.<\/jats:p>","DOI":"10.1165\/rcmb.2012-0182oc","type":"journal-article","created":{"date-parts":[[2013,3,15]],"date-time":"2013-03-15T04:09:02Z","timestamp":1363320542000},"page":"647-654","source":"Crossref","is-referenced-by-count":55,"title":["CCR2 Deficiency, Dysregulation of Notch Signaling, and Spontaneous Pulmonary Arterial Hypertension"],"prefix":"10.1093","volume":"48","author":[{"given":"Yen-Rei A.","family":"Yu","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Mao","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude A.","family":"Piantadosi","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Gunn","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,5,1]]},"reference":[{"key":"2026021904200652200_bib1","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1056\/NEJMra035488","article-title":"Pulmonary arterial hypertension","volume":"351","author":"Farber","year":"2004","journal-title":"N Engl J Med"},{"key":"2026021904200652200_bib2","author":"Southgate"},{"key":"2026021904200652200_bib3","doi-asserted-by":"crossref","first-page":"278","DOI":"10.7326\/0003-4819-148-4-200802190-00006","article-title":"Narrative review: the enigma of pulmonary arterial hypertension: new insights from genetic studies","volume":"148","author":"Newman","year":"2008","journal-title":"Ann Intern Med"},{"key":"2026021904200652200_bib4","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1136\/thx.2008.106435","article-title":"Contribution of inflammation to the pathology of idiopathic pulmonary arterial hypertension in children","volume":"64","author":"Hall","year":"2009","journal-title":"Thorax"},{"issue":"1 Suppl","key":"2026021904200652200_bib5","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/j.jacc.2009.04.006","article-title":"Inflammation, growth factors, and pulmonary vascular remodeling","volume":"54","author":"Hassoun","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"2026021904200652200_bib6","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.devcel.2005.09.010","article-title":"Hypoxia requires Notch signaling to maintain the undifferentiated cell state","volume":"9","author":"Gustafsson","year":"2005","journal-title":"Dev Cell"},{"key":"2026021904200652200_bib7","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/nm.2021","article-title":"Notch3 signaling promotes the development of pulmonary arterial hypertension","volume":"15","author":"Li","year":"2009","journal-title":"Nat Med"},{"key":"2026021904200652200_bib8","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1161\/CIRCRESAHA.108.184846","article-title":"Notch3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed Jagged1","volume":"104","author":"Liu","year":"2009","journal-title":"Circ Res"},{"key":"2026021904200652200_bib9","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1183\/09031936.00002507","article-title":"The pressure mounts on lung dendritic cells","volume":"29","author":"Lambrecht","year":"2007","journal-title":"Eur Respir J"},{"key":"2026021904200652200_bib10","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1097\/CRD.0b013e3181cd612f","article-title":"Inflammation and pulmonary hypertension","volume":"18","author":"Mathew","year":"2010","journal-title":"Cardiol Rev"},{"issue":"6 Suppl","key":"2026021904200652200_bib11","doi-asserted-by":"crossref","first-page":"583S","DOI":"10.1378\/chest.128.6_suppl.583S","article-title":"Circulating mononuclear cells with a dual, macrophage-fibroblast phenotype contribute robustly to hypoxia-induced pulmonary adventitial remodeling","volume":"128","author":"Frid","year":"2005","journal-title":"Chest"},{"key":"2026021904200652200_bib12","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1164\/rccm.201008-1303OC","article-title":"A central role for CD68(+) macrophages in hepatopulmonary syndrome: reversal by macrophage depletion","volume":"183","author":"Thenappan","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021904200652200_bib13","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/nri3070","article-title":"Monocyte recruitment during infection and inflammation","volume":"11","author":"Shi","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"2026021904200652200_bib14","doi-asserted-by":"crossref","first-page":"6915","DOI":"10.4049\/jimmunol.175.10.6915","article-title":"Differentiation to the CCR2+ inflammatory phenotype in vivo is a constitutive, time-limited property of blood monocytes and is independent of local inflammatory mediators","volume":"175","author":"Xu","year":"2005","journal-title":"J Immunol"},{"key":"2026021904200652200_bib15","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.4049\/jimmunol.180.4.2562","article-title":"CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality","volume":"180","author":"Lin","year":"2008","journal-title":"J Immunol"},{"key":"2026021904200652200_bib16","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1161\/CIRCULATIONAHA.110.978627","article-title":"Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension","volume":"123","author":"Vergadi","year":"2011","journal-title":"Circulation"},{"key":"2026021904200652200_bib17","doi-asserted-by":"crossref","first-page":"34342","DOI":"10.1074\/jbc.M109.042671","article-title":"CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization","volume":"284","author":"Roca","year":"2009","journal-title":"J Biol Chem"},{"key":"2026021904200652200_bib18","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1164\/rccm.200610-1559OC","article-title":"Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension","volume":"176","author":"Sanchez","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021904200652200_bib19","doi-asserted-by":"crossref","first-page":"H2021","DOI":"10.1152\/ajpheart.00919.2001","article-title":"Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats","volume":"283","author":"Ikeda","year":"2002","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2026021904200652200_bib20","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.4049\/jimmunol.0901316","article-title":"The CCL7\u2013CCL2\u2013CCR2 axis regulates IL-4 production in lungs and fungal immunity","volume":"183","author":"Szymczak","year":"2009","journal-title":"J Immunol"},{"key":"2026021904200652200_bib21","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/ni.1707","article-title":"Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute T helper type 1 immune responses","volume":"10","author":"Nakano","year":"2009","journal-title":"Nat Immunol"},{"key":"2026021904200652200_bib22","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1164\/rccm.201112-2178ED","article-title":"Drumming up prognostic significance in a heartbeat in pulmonary arterial hypertension","volume":"185","author":"Hassoun","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021904200652200_bib23","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.jvs.2004.07.012","article-title":"CCR2\u2212\/\u2212 knockout mice revascularize normally in response to severe hindlimb ischemia","volume":"40","author":"Tang","year":"2004","journal-title":"J Vasc Surg"},{"key":"2026021904200652200_bib24","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/2040-2384-1-8","article-title":"Novel insights into the differential functions of Notch ligands in vascular formation","volume":"1","author":"Kume","year":"2009","journal-title":"J Angiogenes Res"},{"key":"2026021904200652200_bib25","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1016\/j.cell.2009.03.025","article-title":"The Notch ligands DLL4 and Jagged1 have opposing effects on angiogenesis","volume":"137","author":"Benedito","year":"2009","journal-title":"Cell"},{"key":"2026021904200652200_bib26","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1161\/01.ATV.0000060892.81529.8F","article-title":"Notch signaling in vascular development","volume":"23","author":"Iso","year":"2003","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026021904200652200_bib27","doi-asserted-by":"crossref","first-page":"14542","DOI":"10.1074\/jbc.M802139200","article-title":"Monocyte chemotactic protein (MCP)-1 promotes angiogenesis via a novel transcription factor, MCP-1\u2013induced protein (MCPIP)","volume":"283","author":"Niu","year":"2008","journal-title":"J Biol Chem"},{"key":"2026021904200652200_bib28","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1158\/0008-5472.CAN-11-3567","article-title":"CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells","volume":"72","author":"Tsuyada","year":"2012","journal-title":"Cancer Res"},{"key":"2026021904200652200_bib29","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1038\/ncb1205-1159","article-title":"Receptor regulation: beta-arrestin moves up a Notch","volume":"7","author":"Shenoy","year":"2005","journal-title":"Nat Cell Biol"},{"key":"2026021904200652200_bib30","doi-asserted-by":"crossref","first-page":"R651","DOI":"10.1152\/ajpregu.00069.2007","article-title":"Delayed angiogenesis and VEGF production in CCR2\u2212\/\u2212 mice during impaired skeletal muscle regeneration","volume":"293","author":"Ochoa","year":"2007","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2026021904200652200_bib31","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1002\/bies.20736","article-title":"Modulation of VEGF signalling output by the Notch pathway","volume":"30","author":"Siekmann","year":"2008","journal-title":"Bioessays"},{"key":"2026021904200652200_bib32","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/S0008-6363(02)00600-4","article-title":"MCP-1 induces activation of MAP-kinases ERK, JNK and p38 MAPK in human endothelial cells","volume":"56","author":"Werle","year":"2002","journal-title":"Cardiovasc Res"},{"key":"2026021904200652200_bib33","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.jneuroim.2008.05.011","article-title":"The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells","volume":"199","author":"Cho","year":"2008","journal-title":"J Neuroimmunol"},{"key":"2026021904200652200_bib34","first-page":"217","article-title":"The MAPK-dependent regulation of the Jagged\/Notch gene expression by VEGF, BFGF or PPAR gamma mediated angiogenesis in HUVEC","volume":"61","author":"Kiec-Wilk","year":"2010","journal-title":"J Physiol Pharmacol"},{"key":"2026021904200652200_bib35","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1177\/0003319710385335","article-title":"The role of the CCR2 gene polymorphism in abdominal aortic aneurysms","volume":"62","author":"Katrancioglu","year":"2011","journal-title":"Angiology"},{"key":"2026021904200652200_bib36","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/1742-2094-7-87","article-title":"CCL2\/CCR2 and CX3CL1\/CX3CR1 chemokine axes and their possible involvement in age-related macular degeneration","volume":"7","author":"Raoul","year":"2010","journal-title":"J Neuroinflammation"},{"key":"2026021904200652200_bib37","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1002\/jso.21623","article-title":"Genetic polymorphism of CCR2-64I increased the susceptibility of hepatocellular carcinoma","volume":"102","author":"Yeh","year":"2010","journal-title":"J Surg Oncol"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/48\/5\/647\/8483388","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/48\/5\/647\/8483388","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T09:23:20Z","timestamp":1771493000000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/48\/5\/647\/8483388"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,5,1]]},"references-count":37,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2013,5,1]]},"published-print":{"date-parts":[[2013,5,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2012-0182oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,5]]},"published":{"date-parts":[[2013,5,1]]}}}