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C-Kit–Positive Cells Accumulate in Remodeled Vessels of Idiopathic Pulmonary Arterial Hypertension

2011; American Thoracic Society; Volume: 184; Issue: 1 Linguagem: Inglês

10.1164/rccm.201006-0905oc

1535-4970

David Montani, Frédéric Perros, Natalia Gambaryan, Barbara Girerd, Peter Dorfmüller, Laura Price, Alice Huertas, Hamida Hammad, Bart N. Lambrecht, Gérald Simonneau, Jean‐Marie Launay, Sylvia Cohen‐Kaminsky, Marc Humbert,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

C-kit(+) cells, including bone marrow (BM)-derived progenitors and mast cells, may participate in vascular remodelling. Because recent studies suggest that c-kit may be a target for innovative therapies in experimental pulmonary hypertension, we investigated the contribution of c-kit(+) cells in human idiopathic pulmonary arterial hypertension (IPAH).To investigate the contribution of c-kit(+) cells in human IPAH.Single c-kit, CXCL12/SDF-1α, CXCR4, CD34, and multiple c-kit, α-smooth muscle actin (α-SMA) and tryptase immunostainings were performed in IPAH lungs. C-kit mRNA expression was quantified by real-time polymerase chain reaction in microdissected pulmonary arteries from patients with IPAH and control subjects. Phenotype and function of circulating progenitors were analyzed by flow cytometry. Plasma levels of soluble c-kit and CXCL12/SDF-1α were measured by ELISA.Infiltration of c-kit(+) cells in pulmonary arterial lesions was associated with an increase in c-kit mRNA expression (P < 0.01 compared with control subjects). Both c-kit(+)/tryptase(+) mast cells and c-kit(+)/tryptase(-) BM-derived cells were increased in pulmonary arteries of patients with IPAH compared with control subjects (106.6 ± 54.5 vs. 28 ± 16.8/mm(2) and 143.8 ± 101.1 vs. 23.3 ± 11.9/mm(2); all P<0.01). Plasma-soluble c-kit was increased in IPAH compared with control subjects (27.4 ± 12.4 vs. 19.5 ± 5.8 ng/ml; P<0.05). Two populations of circulating BM-derived cells (lin-CD34(high)CD133(high) [c-kit(high)CXCR4(low)] and lin-CD34(low)CD133(-) [c-kit(low)CXCR4(high)]) were increased in IPAH compared with control subjects (P=0.01). Pulmonary arterial lesions were associated with vasa vasorum expansion expressing CXL12/SDF-1α that may recruit c-kit(+) cells.In IPAH, c-kit(+) cells infiltrate pulmonary arterial lesions and may participate to vascular remodeling. Therefore, c-kit may represent a potential target for innovative PAH therapy.