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Published ahead of print on September 6, 2007, doi:10.1164/rccm.200610-1559OC

Am. J. Respir. Crit. Care Med., Volume 176, Number 10, November 2007, 1041-1047

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Submitted on October 30, 2006
Accepted on September 6, 2007

Role of Endothelium-Derived CC Chemokine Ligand 2 in Idiopathic Pulmonary Arterial Hypertension

Olivier Sanchez1, Elisabeth Marcos1, Frederic Perros2, Elie Fadel3, Ly Tu1, Marc Humbert2, Philippe Dartevelle2, Gerald Simonneau3, Serge Adnot1, and Saadia Eddahibi1*

1 Departement de Physiologie Explorations Fonctionnelles, Hopital H. Mondor, AP-HP, INSERM U841, Creteil, France, 2 Service de Pneumologie, Centre National de Reference de l'Hypertension Arterielle Pulmonaire, Hopital Antoine-Beclere, Assistance-Publique Hopitaux de Paris, Universite Paris-Sud 11, INSERM U764, UPRES EA2705, Clamart, France, 3 Service de Chirurgie Thoracique, Vasculaire et de Transplantation Cardiopulmonaire, Hopital Marie Lannelongue, UPRES EA2705, Le Plessis Robinson, France

* To whom correspondence should be addressed. E-mail: eddahibi{at}im3.inserm.fr.

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 cells (P-ECs) or pulmonary-artery SMCs (PA-SMCs) cultures were measured by ELISA and Western blot analysis. CCL2 receptor CCR2 mRNA levels in monocytes, P-ECs and PASMCs were measured by real-time polymerase chain reaction. Effect of CCL2 on PA-SMCs proliferation and migration was assessed using [3H] thymidine incorporation and modified Boyden's chamber. Effect of EC-derived CCL2 on monocyte migration was measured using modified Boyden's chamber. Measurements and Main Results: Compared to controls, we found in patients with IPAH: elevated CCL2 protein levels in plasma and lung tissue whereas monocyte CCL2 levels were similar between patients and controls; 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 to 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. Conclusion: 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.
Key words: Pulmonary hypertension, endothelial cells, smooth muscle cells, chemokines, CCL2




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