Circulation Research. 2003;92:984-991
Published online before print April 10, 2003, doi: 10.1161/01.RES.0000070587.79937.F0
Published online before print April 10, 2003, doi: 10.1161/01.RES.0000070587.79937.F0
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© 2003 American Heart Association, Inc.
Integrative Physiology |
Protective Role of Angiopoietin-1 in Experimental Pulmonary Hypertension
From Terrence Donnelly Research Laboratories, Division of Cardiology, St Michael’s Hospital and Department of Medicine, University of Toronto, Ontario, Canada.
Correspondence to Duncan J. Stewart, Division of Cardiology, St Michael’s Hospital, 30 Bond St, Suite 7-081 Queen Wing, Toronto, Ontario M5B 1W8, Canada. E-mail stewartd{at}smh.toronto.on.ca
Angiopoietin-1 (Ang-1), a newly discovered ligand of the endothelial-specific tyrosine kinase receptor Tie-2, has been found to promote cell survival, vascular maturation, and stabilization. We hypothesized that Ang-1 gene transfer to the pulmonary microcirculation would improve pulmonary hemodynamics and vascular remodeling in experimental pulmonary hypertension. Rat pulmonary artery smooth muscle cells were transfected with Ang-1 cDNA or null (pFLAG-CMV-1) vector. Syngeneic Fisher 344 rats were treated with monocrotaline (MCT) (75 mg/kg IP) with or without delivery of 5x105 Ang-1–transfected cells into the right jugular vein. After 28 days, plasmid-derived Ang-1 mRNA was consistently and robustly detected by reverse transcriptase–polymerase chain reaction in lungs from all animals receiving Ang-1 gene therapy. Tie-2 receptor expression was markedly downregulated in rats treated with MCT, and this was partially restored by gene therapy with Ang-1. Animals receiving MCT exhibited 77% mortality by 28 days. In contrast, in pAng-1–treated animals, the 28-day mortality was only 14% (P<0.0001). In addition, right ventricular systolic pressure was reduced from 52±1.3 mm Hg in the MCT-treated group to 38±1.3 mm Hg by Ang-1 gene transfer (P<0.01), whereas the measurement of right to left ventricular plus septal weight ratio was also reduced from 0.41±0.03 to 0.31±0.01 (P<0.05). Moreover, MCT resulted in increased apoptosis, mainly in the microvasculature, and reduced endothelial NO synthase mRNA expression, both of which were prevented by Ang-1 gene transfer. Thus, cell-based gene transfer with Ang-1 improved survival and pulmonary hemodynamics in experimental pulmonary hypertension by a mechanism involving the inhibition of apoptosis and protection of the pulmonary microvasculature.
Key Words: gene therapy • angiopoietin-1 • Tie-2 • endothelial nitric oxide synthase • apoptosis
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