The serotonin transporter, gender, and 17β oestradiol in the development of pulmonary arterial hypertension

White, K., Dempsie, Y., Nilsen, M., Wright, A. F., Loughlin, L. and MacLean, M. R. (2011) The serotonin transporter, gender, and 17β oestradiol in the development of pulmonary arterial hypertension. Cardiovascular Research, 90(2), pp. 373-382. (doi:10.1093/cvr/cvq408)

Full text not currently available from Enlighten.

Publisher's URL: http://dx.doi.org/10.1093/cvr/cvq408

Abstract

Aims Idiopathic and familial forms of pulmonary arterial hypertension (PAH) predominantly affect females through an unknown mechanism. Activity of the serotonin transporter (SERT) may modulate the development of PAH, and mice overexpressing SERT (SERT+ mice) develop PAH and severe hypoxia-induced PAH. In the central nervous system, oestrogens influence activity of the serotonin system. Therefore, we examined the influence of gender on the development of PAH in SERT+ mice and how this is modulated by female hormones.

Methods and results PAH was assessed via measurement of right ventricular systolic pressure (RVSP), pulmonary vascular remodelling (PVR), and right ventricular hypertrophy. Male SERT+ mice did not develop PAH. Female SERT+ mice demonstrated increased RVSP and PVR and this was abolished by ovariectomy. Following exposure to hypoxia, SERT+ mice exhibited severe PAH and this was also attenuated by ovariectomy. Chronic administration of 17β oestradiol re-established the PAH phenotype in ovariectomized, normoxic, and hypoxic SERT+ mice. 17β oestradiol also up-regulated tryptophan hydroxylase-1 (TPH1), 5-hydroytryptamine1B (5-HT1B) receptor, and SERT expression in human pulmonary arterial smooth muscle cells (hPASMCs). 17β oestradiol stimulated hPASMC proliferation and this was inhibited by both the TPH inhibitor para-chlorophenylalanine and the 5-HT1B receptor antagonist SB224289.

Conclusion 17β oestradiol is critical to the development of PAH and severe hypoxia-induced PAH in female SERT+ mice. In hPASMCs, 17β oestradiol-induced proliferation is dependant on de novo serotonin synthesis and stimulation of the 5-HT1B receptor. These interactions between the serotonin system and 17β oestradiol may contribute to the increased risk of PAH associated with female gender.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and White, Dr Kevin and Dempsie, Dr Yvonne and Loughlin, Mrs Lynn and Nilsen, Mrs Margaret
Authors: White, K., Dempsie, Y., Nilsen, M., Wright, A. F., Loughlin, L., and MacLean, M. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Cardiovascular Research
Publisher:Oxford University Press
ISSN:0008-6363
ISSN (Online):1755-3245
Published Online:22 December 2010
Related URLs:

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
490991Effect of oestrogen on the serotonin system: role in the development of pulmonary hypertensionMargaret MacLeanMedical Research Council (MRC)G0801171Institute of Cardiovascular and Medical Sciences
536791Effect of oestrogens and oestrogen metabolites on the serotonin system: role in the development of pulmonary hypertensionMargaret MacleanBritish Heart Foundation (BHF)FS/10/019/28205RI CARDIOVASCULAR & MEDICAL SCIENCES
573731Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacleanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES
573733Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacleanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES