Published online before print February 3, 2005, doi: 10.1161/01.RES.0000157672.70560.7b
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© 2005 American Heart Association, Inc.
Integrative Physiology |
Rescue of Monocrotaline-Induced Pulmonary Arterial Hypertension Using Bone Marrow–Derived Endothelial-Like Progenitor Cells
Efficacy of Combined Cell and eNOS Gene Therapy in Established Disease
From the Terrence Donnelly Vascular Biology Laboratories, St Michael’s Hospital and the McLaughlin Center for Molecular Medicine, University of Toronto, Canada.
Correspondence to Dr Duncan J. Stewart, Dexter Hung-Cho Man Chair and Director of the Division of Cardiology, University of Toronto, 30 Bond St, Suite 6-050k Queen Wing, Toronto, Ontario, Canada, M5B 1W8. E-mail stewartd{at}smh.toronto.on.ca
Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance caused by narrowing and loss of pulmonary microvasculature, which in its late stages becomes refractory to traditional therapies. We hypothesized that bone marrow–derived endothelial progenitor cells (EPCs), which normally function to repair and regenerate blood vessels, would restore pulmonary hemodynamics and increase microvascular perfusion in the rat monocrotaline (MCT) model of PAH. Mononuclear cells were isolated from the bone marrow of syngeneic Fisher-344 rats by Ficoll gradient centrifugation and cultured for 7 to 10 days in endothelial growth medium. Fluorescently labeled endothelial-like progenitor cells (ELPCs) engrafted at the level of the distal pulmonary arterioles and incorporated into the endothelial lining in the MCT-injured lung. The administration of ELPCs 3 days after MCT nearly completely prevented the increase in right ventricular systolic pressure seen at 3 weeks with MCT alone (31.5±0.95 versus 48±3 mm Hg, respectively; P<0.001), whereas injection of skin fibroblasts had no protective effect (50.9±5.4 mm Hg). Delayed administration of progenitor cells 3 weeks after MCT prevented the further progression of PAH 2 weeks later (ie, 5 weeks after MCT), whereas only animals receiving ELPCs transduced with human endothelial NO-synthase (eNOS) exhibited significant reversal of established disease at day 35 (31±2 mm Hg, P<0.005) compared with day 21 (50±3 mm Hg). Fluorescent microangiography revealed widespread occlusion of pulmonary precapillary arterioles 3 weeks after MCT, whereas arteriolar-capillary continuity and microvascular architecture was preserved with the administration of syngeneic ELPCs. Moreover, the delivery of ELPCs to rats with established PAH resulted in marked improvement in survival, which was greatest in the group receiving eNOS-transduced cells. We conclude that bone marrow–derived ELPCs can engraft and repair the MCT-damaged lung, restoring microvasculature structure and function. Therefore, the regeneration of lung vascular endothelium by injection of progenitor cells may represent a novel treatment paradigm for patients with PAH.
Key Words: progenitor cells • pulmonary hypertension • endothelium • endothelial nitric oxide synthase
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