PT  - JOURNAL ARTICLE
AU  - Loredana Ciuclan
AU  - Nicholas Duggan
AU  - Martin Hussey
AU  - Robert Good
AU  - Olivier Bonneau
AU  - David Rowlands
AU  - Victoria Burton
AU  - Gabor Jarai
AU  - John Westwick
AU  - Matthew Thomas
TI  - Reduction in serotonin signaling via TPH1 inhibition attenuates the progression of PAH in mice with genetic ablation of endothelial BMPR-II
DP  - 2012 Sep 01
TA  - European Respiratory Journal
PG  - 4554
VI  - 40
IP  - Suppl 56
4099  - http://erj.ersjournals.com/content/40/Suppl_56/4554.short
4100  - http://erj.ersjournals.com/content/40/Suppl_56/4554.full
SO  - Eur Respir J2012 Sep 01; 40
AB  - Introduction. Genetic studies in familial PAH have revealed heterozygous germline mutations in the BMPR2 gene and dysfunction of serotonin (5-HT) signaling has been implicated in other forms of PAH. Here we investigate a genetic model of PAH, where BMPR2 deletion is restricted to endothelial cells (ECs)-BMPR2f/f;ALK1-Cre strain, aiming to determine a relationship between pathologies mediated by 5-HT and BMPR2 signaling.Methods. We investigated the effects of p-chlorophenylalanine (pCPA; 200mg/kg- inhibits 5-HT synthesis by blocking tryptophan hydroxylase (TPH)), on hemodynamics, vascular remodeling and plasma signatures in wild-type (WT) and BMPR2f/f;ALK1-Cre mice (BMPR2-KO) exposed to chronic hypoxia under VEGFR inhibition (SU5416) for 3 weeks.Results. Pathobiology development profile of BMPR2-KO mice at 2 and 5 months of age, demonstrated that the older age group tended to have a higher frequency of increased right ventricular pressure (RVP) and hypertrophy (RVH). 2 month old BMPR2-KO mice exposed to chronic hypoxia/SU5416 developed higher RVP and RVH compared with WT controls. Normoxic WT and BMPR2-KO mice did not display significant changes in the above measurements when compared between groups. Treatment with pCPA reduced all measures of PAH pathology observed in chronic hypoxic/SU5416 treated BMPR2-KO mice. These changes were observed in accordance with a fall in platelet rich plasma 5-HT.Conclusion. Genetic ablation of the BMPR2 gene in pulmonary ECs is sufficient to predispose to PAH. Our data reveal interplay between BMPR2 signaling and the 5-HT system in ECs within PAH, leading to increased susceptibility to PAH progression.