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Endothelin Receptor Blockade Prevents Development of Pulmonary Hypertension in a Mouse Model of Scleroderma

Derrett-Smith, E, Sobanski, V, Trinder, S, Gilbane, A, Iglarz, M, Abraham, D, Holmes, A and Denston, C (2015) Endothelin Receptor Blockade Prevents Development of Pulmonary Hypertension in a Mouse Model of Scleroderma In: Rheumatology 2015: The British Society for Rheumatology and British Health Professionals in Rheumatology Annual Meeting 2015, 2015-04-28 - 2015-04-30, Manchester, UK.

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Abstract

Background: Pulmonary arterial hypertension (PAH) is an important complication of SSc that occurs in around 10% of cases. We have previously shown that a TGFb dependent transgenic mouse strain (TbRIIk-fib) is susceptible to organ based pathology relevant to SSc including development of pulmonary hypertension (PH) after pharmacological pulmonary endothelial injury by SU5416, a VEGF receptor inhibitor. In this study, we have prevented the development of PH in this mouse strain using macitentan, a novel dual ETA/B receptor antagonist recently licensed to treat PAH in CTD based upon a significant effect on morbidity and mortality in PAH. Methods: SU5416, a VEGF receptor inhibitor, was administered to all TbRIIk-fib transgenic (TG) mice and wild-type (WT) littermate controls to induce endothelial injury with subsequent endothelial proliferation and PH in transgenic mice only. Mice were treated with either 50 mg/kg macitentan daily by oral gavage or vehicle alone (n ¼ 8 for each group) either before SU5416 injection or on day 8 following injection. The development of PH in each group was assessed by histology and immunohistochemistry of vessel architecture, in vivo haemodynamic studies and RV mass index measurements. Biochemical responses to TGFb, endothelin and VEGF stimulation before and after macitentan were examined in cultured T bRII k-fib lung fibroblasts. Results: Compared with WT littermates, after SU5416, all TG mice developed a prominent perivascular chronic inflammatory infiltrate and smooth muscle layer hypertrophy, as previously described. RV mass index was elevated in TG animals receiving vehicle compared with other groups (TG vehicle 0.29 0.007, TG macitentan 0.24 0.007, P < 0.05). The increase in RV systolic pressure in TG animals treated with SU5416 was also abrogated by macitentan (TG vehicle 28.8 mmHg 0.72, TG macitentan 22.0 1.62, P < 0.001) without any significant change in systemic arterial blood pressure in any group. Treatment with macitentan after day 8 was sufficient to normalize haemodynamic consequences of SU5416 administration. There was obliterative pulmonary arteriolar occlusion in 21% of vessels in TG mice treated with vehicle. In contrast, no vessels in WT mice or TG mice treated with macitentan developed this histological change. Explanted TG lung fibroblasts showed an increase in proliferation and migration with upregulation of VEGF and TGFb signalling and downregulation of endothelin receptor A compared with WT littermates. Conclusion: Macitentan prevents the development of histological and haemodynamic PH in this mouse model of SSc. These findings suggest a pivotal role for perturbed endothelin activity in the development of PH associated with altered TGFb and VEGF signalling. Our results also validate this model as a platform for experimental therapeutic studies and provide further insight into pathogenic mechanisms of PAH in SSc.

Item Type: Conference or Workshop Item (Conference Abstract)
Authors :
NameEmailORCID
Derrett-Smith, EUNSPECIFIEDUNSPECIFIED
Sobanski, VUNSPECIFIEDUNSPECIFIED
Trinder, Ss.trinder@surrey.ac.ukUNSPECIFIED
Gilbane, AUNSPECIFIEDUNSPECIFIED
Iglarz, MUNSPECIFIEDUNSPECIFIED
Abraham, DUNSPECIFIEDUNSPECIFIED
Holmes, AUNSPECIFIEDUNSPECIFIED
Denston, CUNSPECIFIEDUNSPECIFIED
Date : 30 April 2015
Identification Number : 10.1093/rheumatology/kev090.048
Copyright Disclaimer : The abstracts are freely available online to all visitors to the Rheumatology website (http://www.rheumatology.oxfordjournals.org).
Contributors :
ContributionNameEmailORCID
publisherOxford University Press, UNSPECIFIEDUNSPECIFIED
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:45
Last Modified : 17 May 2017 14:52
URI: http://epubs.surrey.ac.uk/id/eprint/829053

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