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

Full Abstract

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.

Author information

Author/s: Kugathasan, Lakshmi (L); Ray, Julie Basu (JB); Deng, Yupu (Y); Rezaei, Effat (E); Dumont, Daniel J (DJ); Stewart, Duncan J (DJ);

Affiliation: Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: The Journal of experimental medicine (J Exp Med), published in United States. (Language: eng)

Reference: 2009-Sep; vol 206 (issue 10) : pp 2221-34

Dates: Created 2009/10/07; Completed 2009/10/22;

PMID: 19737862, status: MEDLINE (last retrieval date: 10/22/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Interleukin-6 - pharmacology
Mice
Mice, Transgenic
Phenotype
Pulmonary Artery - pathology
Receptor Protein-Tyrosine Kinases - physiology
Serotonin - pharmacology
Signal Transduction
Systole - drug effects

Associated Chemicals: Angiopoietin-1 (0) ; Interleukin-6 (0) ; Serotonin (50-67-9) ; Tek protein, mouse (EC 2.7.1.-) ; Receptor Protein-Tyrosine Kinases (EC 2.7.1.112) ; Bmpr2 protein, mouse (EC 2.7.1.37) ; Bone Morphogenetic Protein Receptors, Type II (EC 2.7.1.37) ; Caspases (EC 3.4.22.-)

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