title: CCR2 deficiency, dysregulation of Notch signaling, and spontaneous pulmonary arterial hypertension.
abstract: 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(-/-)) mice to chronic hypobaric hypoxia to induce PAH. After hypoxic stress, Ccr2(-/-) 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(-/-) 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(-/-) mice during either normoxia or hypoxia. However, Ccr2(-/-) 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.
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Yen-Rei A
authors.initials: YR
authors.lastname: Yu
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gunn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001160:Arterioles / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D065627:Familial Primary Pulmonary Hypertension; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications / Q000276:immunology / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072101:Jagged-2 Protein; D008168:Lung / Q000098:blood supply; D008264:Macrophages / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D000071656:Receptor, Notch3; D054390:Receptors, CCR2 / Q000172:deficiency* / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C515335:Ccr2 protein, mouse; C519665:DLL4 protein, mouse; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C490503:Jag2 protein, mouse; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D054390:Receptors, CCR2; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins