Effect of oestrogen on the serotonin system : role in the development of pulmonary hypertension

Pulmonary hypertension occurs when the blood vessels of the lung close down. It is a fatal disease with patients dying within 3-5 years of diagnosis. It occurs more in females than males yet the reason for this is unknown. We have identified a possible reason for this. Serotonin is a chemical produced primarily by the gut but also by the lungs. It has a variety of effects including the ability to close down the blood vessels of the lungs. During pulmonary hypertension the activity of the serotonin system is increased. In mice models of pulmonary hypertension where the serotonin system is artificially increased, it is female mice that develop pulmonary hypertension. We wish to investigate if the female hormone oestrogen interacts with serotonin in such a way as to promote the development of pulmonary hypertension.

Both idiopathic pulmonary hypertension (PAH) and familial PAH occur more in females than in males. We will test the following hypothesis: ?Serotonergic and oestradiol pathways converge and interact and this underlies gender differences in the development of pulmonary hypertension.? We will study models of PAH in which there is an increased activity of the serotonin system. These are mice that over-expression the serotonin transporter (SERT+ mice) and mice treated with dexfenfluramine (Dfen). Female SERT+ mice develop much greater PAH than male SERT+ mice and male mice do not develop Dfen-induced PAH. Hence SERT+ mice and Dfen ?treated mice will be used to test the hypothesis. We will determine if ovariectomy (Oce) will abolish the PAH phenotype observed in female SERT+ mice before and after exposure to hypoxia. PAH will be assessed by measuring pulmonary pressures and resistance in vivo (under anaesthesia) as well as right ventricular hypertrophy and pulmanary vascular remodelling. We will also investigate if Oce will abolish Dfen-induced PAH in female mice and if Ove affects the expression of elements of the serotonin system in pulmonary arteries (e.g. SERT, receptors, tryptophan hydroxylase). We will investigate if oestrogen will induce a PAH phenotype in male SERT+ mice or male mice treated with Dfen. We will also investigate what genes are differentially regulated by gender, SERT over-expression and Dfen-administration by Affymetrix GeneChip array analysis. Using cultures of pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery fibroblasts (PAFs) we will determine if oestrogen influences the serotonin system (and related signalling pathways). We will examine further the effects that over-expression of SERT, or Dfen administration may have on the ability of E2 to induce proliferation (or enhance serotonin-induced proliferation) in PASMCs and PAFs. This research falls into two current MRC priority areas 1. respiratory medicine ? SERT gene polymorphism determines the severity of PAH in hypoxemic patients with COPD and women have more severe COPD and greater COPD-associated mortality. Hence this research addresses the aetiology of COPD and the biological basis for the observed variation in disease progression. 2. integrative physiology ? this work integrates whole animal research with gene analysis and cellular studies with the aim to help promote understanding of normal function and the physiology of PAH.