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


OBJECTIVE
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.


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.
Sanchez
Olivier
O
INSERM U841 and Département de Physiologie Explorations Fonctionnelles, Hôpital H. Mondor, AP-HP, Créteil, France.
Marcos
Elisabeth
E
Perros
Frédéric
F
Fadel
Elie
E
Tu
Ly
L
Humbert
Marc
M
Dartevelle
Philippe
P
Simonneau
Gérald
G
Adnot
Serge
S
Eddahibi
Saadia
S
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018929:Cell Culture Techniques; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism*; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism