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A correction to this article has been published: Kugathasan et al., J. Exp. Med. 0 (2009) jem.20090389102109cv3
Published online
doi:10.1084/jem.20090389
The Journal of Experimental Medicine, Vol. 206, No. 10, 2221-2234
The Rockefeller University Press, 0022-1007 $30.00
© Kugathasan et al.
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ARTICLE

 The angiopietin-1–Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic mice

Lakshmi Kugathasan1,3, Julie Basu Ray2,3, Yupu Deng3,4, Effat Rezaei3, Daniel J. Dumont5, and Duncan J. Stewart1,3,4

1 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada
2 Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada
3 Terrence Donnelly Vascular Biology Laboratories, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada
4 Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada
5 Department of Medical Biophysics, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario M4N 3M5, Canada

CORRESPONDENCE Duncan J. Stewart: djstewart{at}ohri.ca

The role of the angiopoietin-1 (Ang1)–Tie2 pathway in the pathogenesis of pulmonary arterial hypertension (PAH) is controversial. Although Ang1 is well known to prevent endothelial activation and injury in systemic vascular beds, this pathway has been suggested to mediate pulmonary vascular remodeling in PAH. Therefore, we used transgenic models to determine the effect of increased or decreased Tie2 activity on the development of PAH. We now report modest spontaneous elevation in right ventricular systolic pressure in Tie2-deficient mice (Tie2+/–) compared with wild-type (WT) littermate controls, which was exacerbated upon chronic exposure to the clinically relevant PAH triggers, serotonin (5-HT) or interleukin-6 (IL-6). Moreover, overexpression of Ang1 in transgenic mice had no deleterious effect on pulmonary hemodynamics and, if anything, blunted the response to 5-HT. Exposure to 5-HT or IL-6 also decreased lung Ang1 expression, further reducing Tie2 activity and inducing pulmonary apoptosis in the Tie2+/– group only. Similarly, cultured pulmonary artery endothelial cells subjected to Tie2 silencing demonstrated increased susceptibility to apoptosis after 5-HT treatment. Finally, treatment of Tie2-deficient mice with Z-VAD, a pan-caspase inhibitor, prevented the pulmonary hypertensive response to 5-HT. Thus, these findings firmly establish that endothelial survival signaling via the Ang1–Tie2 pathway is protective in PAH.

Abbreviations used: 5-HT, serotonin; Ang, angiopoietin; BT, binary transgenic; EC, endothelial cell; eNOS, endothelial NO synthase; NBT, non-BT; PAH, pulmonary arterial hypertension; PI, propidium iodide; RV, right ventricle; RVSP, right ventricular systolic pressure; SBP, systolic blood pressure; sIL-6R, soluble IL-6R; SMC, smooth muscle cell; TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling.

© 2009 Kugathasan et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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