RT Journal Article SR Electronic T1 Reduction in serotonin signaling via TPH1 inhibition attenuates the progression of PAH in mice with genetic ablation of endothelial BMPR-II JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 4554 VO 40 IS Suppl 56 A1 Loredana Ciuclan A1 Nicholas Duggan A1 Martin Hussey A1 Robert Good A1 Olivier Bonneau A1 David Rowlands A1 Victoria Burton A1 Gabor Jarai A1 John Westwick A1 Matthew Thomas YR 2012 UL http://erj.ersjournals.com/content/40/Suppl_56/4554.abstract 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.