C-kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension

Am J Respir Crit Care Med. 2011 Jul 1;184(1):116-23. doi: 10.1164/rccm.201006-0905OC. Epub 2011 Feb 4.


Rationale: 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).

Objectives: To investigate the contribution of c-kit(+) cells in human IPAH.

Methods: 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.

Measurements and main results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD34 / metabolism
  • Chemokine CXCL12 / metabolism
  • Connective Tissue / metabolism
  • Flow Cytometry
  • Humans
  • Hypertension, Pulmonary / metabolism
  • Hypertension, Pulmonary / pathology*
  • Hypertension, Pulmonary / physiopathology
  • Immunohistochemistry
  • Mast Cells / metabolism
  • Mast Cells / pathology
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Pulmonary Artery / metabolism*
  • Pulmonary Artery / pathology
  • Pulmonary Artery / physiopathology
  • Receptors, CXCR4 / metabolism
  • Stem Cells / metabolism*
  • Stem Cells / pathology
  • Tryptases / metabolism
  • Vasa Vasorum / metabolism


  • Antigens, CD34
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Receptors, CXCR4
  • Proto-Oncogene Proteins c-kit
  • Tryptases