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CCR2 deficiency, dysregulation of Notch signaling, and spontaneous pulmonary arterial hypertension.

Publication ,  Journal Article
Yu, Y-RA; Mao, L; Piantadosi, CA; Gunn, MD
Published in: Am J Respir Cell Mol Biol
May 2013

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.

Duke Scholars

Published In

Am J Respir Cell Mol Biol

DOI

EISSN

1535-4989

Publication Date

May 2013

Volume

48

Issue

5

Start / End Page

647 / 654

Location

United States

Related Subject Headings

  • Signal Transduction
  • Serrate-Jagged Proteins
  • Respiratory System
  • Receptors, Notch
  • Receptors, CCR2
  • Receptor, Notch3
  • Muscle, Smooth, Vascular
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Yu, Y.-R., Mao, L., Piantadosi, C. A., & Gunn, M. D. (2013). CCR2 deficiency, dysregulation of Notch signaling, and spontaneous pulmonary arterial hypertension. Am J Respir Cell Mol Biol, 48(5), 647–654. https://doi.org/10.1165/rcmb.2012-0182OC
Yu, Yen-Rei A., Lan Mao, Claude A. Piantadosi, and Michael D. Gunn. “CCR2 deficiency, dysregulation of Notch signaling, and spontaneous pulmonary arterial hypertension.Am J Respir Cell Mol Biol 48, no. 5 (May 2013): 647–54. https://doi.org/10.1165/rcmb.2012-0182OC.
Yu Y-RA, Mao L, Piantadosi CA, Gunn MD. CCR2 deficiency, dysregulation of Notch signaling, and spontaneous pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2013 May;48(5):647–54.
Yu, Yen-Rei A., et al. “CCR2 deficiency, dysregulation of Notch signaling, and spontaneous pulmonary arterial hypertension.Am J Respir Cell Mol Biol, vol. 48, no. 5, May 2013, pp. 647–54. Pubmed, doi:10.1165/rcmb.2012-0182OC.
Yu Y-RA, Mao L, Piantadosi CA, Gunn MD. CCR2 deficiency, dysregulation of Notch signaling, and spontaneous pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2013 May;48(5):647–654.

Published In

Am J Respir Cell Mol Biol

DOI

EISSN

1535-4989

Publication Date

May 2013

Volume

48

Issue

5

Start / End Page

647 / 654

Location

United States

Related Subject Headings

  • Signal Transduction
  • Serrate-Jagged Proteins
  • Respiratory System
  • Receptors, Notch
  • Receptors, CCR2
  • Receptor, Notch3
  • Muscle, Smooth, Vascular
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice