The angiopietin-1-Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic mice.
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.
Kugathasan
Lakshmi
L
Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada.
Ray
Julie Basu
JB
Deng
Yupu
Y
Rezaei
Effat
E
Dumont
Daniel J
DJ
Stewart
Duncan J
DJ
D042683:Angiopoietin-1 / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000502:physiology; D061945:Caspase Inhibitors; D042783:Endothelial Cells / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011651:Pulmonary Artery / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D042787:Receptor, TIE-2; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction; D013599:Systole / Q000187:drug effects
D042683:Angiopoietin-1; D061945:Caspase Inhibitors; D015850:Interleukin-6; D012701:Serotonin; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II