Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension

Am J Respir Crit Care Med. 2007 Nov 15;176(10):1041-7. doi: 10.1164/rccm.200610-1559OC. Epub 2007 Sep 6.


Rationale: Inflammatory cytokines may affect pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH). CC chemokine ligand 2 (CCL2) is synthesized by vascular cells and can stimulate monocyte/macrophage migration and smooth muscle cell (SMC) proliferation.

Objectives: To investigate the role of CCL2 in IPAH.

Methods: CCL2 levels in plasma, monocytes, lungs, and medium from pulmonary endothelial cell (P-EC) or pulmonary artery SMC (PA-SMC) cultures were measured by ELISA and Western blot analysis. CCL2 receptor CCR2 mRNA levels in monocytes, P-ECs, and PA-SMCs were measured by real-time polymerase chain reaction. Effect of CCL2 on PA-SMC proliferation and migration was assessed using [3H]thymidine incorporation and a modified Boyden's chamber. The effect of endothelial cell-derived CCL2 on monocyte migration was measured using a modified Boyden's chamber.

Measurements and main results: Compared with control subjects, we found the following in patients with IPAH: elevated CCL2 protein levels in plasma and lung tissue, whereas monocyte CCL2 levels were similar between patients and control subjects, and elevated CCL2 release by P-ECs or PA-SMCs. P-ECs released twice as much CCL2 than did PA-SMCs. Monocyte migration was markedly increased in the presence of P-ECs, and the increase was larger with P-ECs from patients with IPAH. CCL2-blocking antibodies reduced P-ECs' chemotactic activity by 60%. Compared with controls, PA-SMCs from patients exhibited stronger migratory and proliferative responses to CCL2, in keeping with the finding that CCR2 was markedly increased in PA-SMCs from patients.

Conclusions: These results suggest that CCL2 overproduction may be a feature of the abnormal P-EC phenotype in IPAH, contributing to the inflammatory process and to pulmonary vascular remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • Cell Culture Techniques
  • Cell Movement
  • Cell Proliferation
  • Chemokine CCL2 / metabolism*
  • Endothelial Cells / physiology*
  • Female
  • Humans
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / pathology
  • Male
  • Middle Aged
  • Monocytes / physiology
  • Myocytes, Smooth Muscle / physiology*
  • RNA, Messenger / metabolism
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism


  • CCL2 protein, human
  • CCR2 protein, human
  • Chemokine CCL2
  • RNA, Messenger
  • Receptors, CCR2