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Evidence of Dysfunction of Endothelial Progenitors in Pulmonary Arterial Hypertension

¹ Papworth Hospital and ² University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom; ³ Department of Internal Medicine, University of Giessen Lung Center, Giessen, Germany; ⁴ Hammersmith Hospital, London and ⁵ Royal United Hospital, Bath, United Kingdom; ⁶ Department Antibody Technology, ImClone Systems, Inc., New York; and ⁷ Department of Medicine, University Hospital Eppendorf, Hamburg, Germany

Correspondence and requests for reprints should be addressed to Nicholas W. Morrell, M.D., Department of Medicine, University of Cambridge School of Clinical Medicine, Box 157, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: nwm23{at}cam.ac.uk

Rationale: 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.

Objectives: 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.

Key Words: pulmonary hypertension • endothelial progenitor

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Although cells bearing markers suggesting a progenitor phenotype have been described in patients with pulmonary arterial hypertension (PAH), the role of endothelial progenitor cells (EPCs) in the pathobiology of PAH is controversial. What This Study Adds to the Field Dysfunctional endothelial progenitor cells in mutations in bone morphogenetic protein type II receptor are associated with PAH, and engraftment of EPCs can be found in vascular lesions of these patients. These observations are of importance for ongoing work examining potential roles for EPCs in the pathogenesis of lung vascular disease in PAH.

 

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