Protective role of angiopoietin-1 in experimental pulmonary hypertension.
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 5x10(5) 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.
Zhao
Yidan D
YD
Terrence Donnelly Research Laboratories, Division of Cardiology, St Michael's Hospital and University of Toronto, Ontario, Canada.
Campbell
Andrew I M
AI
Robb
Malcolm
M
Ng
Douglas
D
Stewart
Duncan J
DJ
D043925:Angiogenesis Inducing Agents / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D053148:Caspase 3; D020169:Caspases / Q000032:analysis / Q000378:metabolism; D017690:Cell Transplantation; D002478:Cells, Cultured; D019610:Cytoprotection; D015316:Genetic Therapy; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2; D014162:Transfection; D019076:Transgenes; D017725:Ventricular Pressure
D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467629:Angpt1 protein, rat; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D016686:Monocrotaline; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases