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Published ahead of print on March 16, 2006, doi:10.1165/rcmb.2005-0115OC

Am. J. Respir. Cell Mol. Biol., Volume 35, Number 2, August 2006, 182-189

A more recent version of this article appeared on August 1, 2006
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Submitted on March 23, 2005
Revised on March 16, 2006

Microvascular Regeneration in Established Pulmonary Hypertension by Angiogenic Gene Transfer

Yidan D Zhao1, David W Courtman2, Douglas S Ng2, Malcolm J Robb2, Yupu P Deng2, Judy Trogadis2, Robin N.N. Han2, and Duncan J Stewart2*

1 Department of Pharmacology, University of Illinois, Chicago, IL, USA, 2 Cardiology Lab, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada

* To whom correspondence should be addressed. E-mail: stewartd{at}smh.toronto.on.ca.

Pulmonary arterial hypertension (PAH) is characterized by widespread loss of pulmonary microvasculature. Therefore we hypothesized that angiogenic gene therapy would reverse established PAH, in part restoring the lung microcirculation. Methods and Results: Three weeks after monocrotaline (MCT) treatment, Fisher 344 rats were randomized to receive a total of either 1.5 x 106 syngeneic fibroblasts (FB) transfected with vascular endothelial growth factor A (VEGF), endothelial NO-synthase (eNOS), or null-plasmid transfected FBs. Right ventricular systolic pressure (RVSP) was similarly increased in all MCT-treated groups at the time of gene transfer. Animals receiving the null-vector progressed to severe PAH by day 35 (p<0.001). In contrast, eNOS gene transfer significantly reduced RVSP at day 35 compared to day 21, whereas VEGF prevented further increases in RVSP over the subsequent 2 weeks but did not reverse established PAH. RV hypertrophy was significantly reduced in both the eNOStreated and VEGF-treated groups compared with the null-transfected controls. Fluorescent microangiography revealed widespread occlusion of the pre-capillary arterioles 21 days after MCT treatment, and animals receiving eNOS gene transfer exhibited the greatest improvement in the arteriolar architecture and capillary perfusion at day 35. Conclusions: Cell-based eNOS gene transfer was more effective than VEGF in reversing established PAH, associated with evidence of regeneration of pulmonary microcirculation.




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