Submitted on January 14, 2006
Accepted on January 26, 2007
Bone morphogenetic protein type 2 receptor (BMPR2) gene therapy attenuates hypoxic pulmonary hypertension
Ann Michelle Reynolds1, Wei Xia2, Mark D Holmes3, SANDRA J HODGE4, Sergei Danilov5, David T Curiel6, Nicholas W Morrell7, and Paul N Reynolds3*
1 Lung Research Laboratory, Royal Adelaide Hospital, Adelaide, Australia; Lung Research Laboratory, Hanson Institute, Adelaide, Australia
2 Lung Research Laboratory, Hanson Institute, Adelaide, Australia; Department of Medicine, University of Adelaide, Adelaide, Australia
3 Lung Research Laboratory, Royal Adelaide Hospital, Adelaide, Australia; Lung Research Laboratory, Hanson Institute, Adelaide, Australia; Department of Medicine, University of Adelaide, Adelaide, Australia
4 Lung Research Laboratory, Hanson Institute, Royal Adelaide Hospital, ADELAIDE, South Australia, Australia
5 Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois, United States
6 Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama, United States
7 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooe's and Papworth Hospitals, Cambridge, United Kingdom
* To whom correspondence should be addressed. E-mail: Paul.Reynolds{at}adelaide.edu.au.
Idiopathic pulmonary arterial hypertension (PAH) is characterised by proliferation of pulmonary vascular endothelial and smooth muscle cells causing increased vascular resistance and right heart failure. Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) are believed to cause the familial form of the disease. Reduced expression of BMPR2 is also noted in secondary PAH. Recent advances in the therapy of PAH have improved quality of life and survival, but many patients continue to do poorly. The possibility of treating PAH via improving BMPR2 signalling is thus a rational consideration. Such an approach could be synergistic with or additive to current treatments. We developed adenoviral vectors containing the BMPR2 gene. Transfection of cells in vitro resulted in upregulation of SMAD signalling and reduced cell proliferation. Targeted delivery of vector to the pulmonary vascular endothelium of rats substantially reduced the pulmonary hypertensive response to chronic hypoxia, as reflected by reductions in pulmonary artery and right ventricular pressures, right ventricular hypertrophy and muscularisation of distal pulmonary arterioles. These data provide further evidence for a role for BMPR2 in PAH and provide a rationale for the development of therapies aimed at improving BMPR2 signalling.
