Protective Role of Angiopoietin-1 in Experimental Pulmonary Hypertension

• Published in: Circulation research Vol. 92; no. 9; pp. 984 - 991
• Main Authors: Zhao, Yidan D, Campbell, Andrew I.M, Robb, Malcolm, Ng, Douglas, Stewart, Duncan J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 16.05.2003; Lippincott; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Angiogenesis Inducing Agents - biosynthesis; Angiogenesis Inducing Agents - genetics; Angiogenesis Inducing Agents - physiology; Angiopoietin-1; Angiopoietin-2; Animals; Apoptosis; Biological and medical sciences; Biotechnology; Body Weight; Caspase 3; Caspases - analysis; Caspases - metabolism; Cell Transplantation; Cells, Cultured; Cytoprotection; Fundamental and applied biological sciences. Psychology; Gene therapy; Genetic Therapy; Health. Pharmaceutical industry; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - therapy; Industrial applications and implications. Economical aspects; Lung - metabolism; Lung - pathology; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Monocrotaline; Muscle, Smooth, Vascular - cytology; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type III; Rats; Rats, Inbred F344; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, TIE-2; RNA, Messenger - biosynthesis; Transfection; Transgenes; Ventricular Pressure; Animal model; Rat; Ligand; Tie-2; Vascular remodeling; Microcirculation; Pulmonary vessel; Blood vessel; endothelial nitric oxide synthase; Protection; Protein-tyrosine kinase; Biological receptor; angiopoietin-1; Enzyme; Transferases; Rodentia; Gene expression; Pulmonary hypertension; Nitric-oxide synthase; Endothelium; Vertebrata; Mammalia; Animal; Circulatory system; Oxidoreductases; Gene therapy; Apoptosis
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000070587.79937.F0

ABSTRACT—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 5×10 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.