Targeting of c-kit+ haematopoietic progenitor cells prevents hypoxic pulmonary hypertension.
Haematopoietic c-kit+ progenitor cells may contribute to pulmonary vascular remodelling and pulmonary hypertension (PH). Stromal derived factor-1 (SDF-1/CXCL12) and its receptors CXCR4 and CXCR7 have been shown to be critical for homing and mobilisation of haematopoietic c-kit+ progenitor cells in the perivascular niche. We administered AMD3100, a CXCR4 antagonist, and CCX771, a CXCR7 antagonist, to chronic hypoxia exposed mice in order to study the role of c-kit+ progenitor cells in PH. CXCL12, CXCR4 and CXCR7 protein expression, haemodynamic parameters, right ventricular mass, extent of vascular remodelling and perivascular progenitor cell accumulation were studied. Chronic hypoxia-exposed mice showed increased total lung tissue expression of CXCR4, CXCR7 and CXCL12 after development of PH. This was associated with significantly increased right ventricular systolic pressure and evidence of right ventricular hypertrophy, vascular remodelling and perivascular c-kit+/sca-1+ progenitor cell accumulation. CCX771 administration did not abrogate these effects. In contrast, administration of AMD3100, whether alone or combined with CCX771, prevented vascular remodelling, PH and perivascular accumulation of c-kit+/sca-1+ progenitor cells, with a synergistic effect of these agents. This study offers important pathophysiological insights into the role of haematopoietic c-kit+ progenitors in hypoxia-induced vascular remodelling and may have therapeutic implications for PH.
Gambaryan
N
N
Faculté de médecine, Université Paris-Sud, Kremlin-Bicêtre, France.
Perros
F
F
Montani
D
D
Cohen-Kaminsky
S
S
Mazmanian
M
M
Renaud
J-F
JF
Simonneau
G
G
Lombet
A
A
Humbert
M
M
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000096:biosynthesis; D000080027:Cyclams; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006571:Heterocyclic Compounds / Q000008:administration & dosage*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000098:blood supply; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D054387:Receptors, CXCR / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000950:Antigens, Ly; D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D019009:Proto-Oncogene Proteins c-kit; C088327:plerixafor