Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension.
BACKGROUND
Severe pulmonary arterial hypertension (PAH) is characterized by the formation of plexiform lesions and concentric intimal fibrosis in small pulmonary arteries. The origin of cells contributing to these vascular lesions is uncertain. Endogenous endothelial progenitor cells are potential contributors to this process.


OBJECTIVE
To determine whether progenitors are involved in the pathobiology of PAH.


METHODS
We performed immunohistochemistry to determine the expression of progenitor cell markers (CD133 and c-Kit) and the major homing signal pathway stromal cell-derived factor-1 and its chemokine receptor (CXCR4) in lung tissue from patients with idiopathic PAH, familial PAH, and PAH associated with congenital heart disease. Two separate flow cytometric methods were employed to determine peripheral blood circulating numbers of angiogenic progenitors. Late-outgrowth progenitor cells were expanded ex vivo from the peripheral blood of patients with mutations in the gene encoding bone morphogenetic protein receptor type II (BMPRII), and functional assays of migration, proliferation, and angiogenesis were undertaken. measurements and main results: There was a striking up-regulation of progenitor cell markers in remodeled arteries from all patients with PAH, specifically in plexiform lesions. These lesions also displayed increased stromal cell-derived factor-1 expression. Circulating angiogenic progenitor numbers in patients with PAH were increased compared with control subjects and functional studies of late-outgrowth progenitor cells from patients with PAH with BMPRII mutations revealed a hyperproliferative phenotype with impaired ability to form vascular networks.


CONCLUSIONS
These findings provide evidence of the involvement of progenitor cells in the vascular remodeling associated with PAH. Dysfunction of circulating progenitors in PAH may contribute to this process.
Toshner
Mark
M
Papworth Hospital, Cambridge, United Kingdom.
Voswinckel
Robert
R
Southwood
Mark
M
Al-Lamki
Rafia
R
Howard
Luke S G
LS
Marchesan
Denis
D
Yang
Jun
J
Suntharalingam
Jay
J
Soon
Elaine
E
Exley
Andrew
A
Stewart
Susan
S
Hecker
Markus
M
Zhu
Zhenping
Z
Gehling
Ursula
U
Seeger
Werner
W
Pepke-Zaba
Joanna
J
Morrell
Nicholas W
NW
D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000502:physiology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000503:physiopathology*; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics*; D011651:Pulmonary Artery; D013234:Stem Cells / Q000502:physiology
D052006:Bone Morphogenetic Protein Receptors, Type II