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

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 17 beta oestradiol re-established the PAH phenotype in ovariectomized, normoxic, and hypoxic SERT+ mice. 17b oestradiol also upregulated tryptophan hydroxylase-1 (TPH1), 5-hydroytryptamine(1B) (5-HT1B) receptor, and SERT expression in human pulmonary arterial smooth muscle cells (hPASMCs). 17 beta oestradiol stimulated hPASMC proliferation and this was inhibited by both the TPH inhibitor para-chlorophenylalanine and the 5-HT1B receptor antagonist SB224289. Conclusion 17 beta oestradiol is critical to the development of PAH and severe hypoxia-induced PAH in female SERT+ mice. In hPASMCs, 17 beta oestradiol-induced proliferation is dependant on de novo serotonin synthesis and stimulation of the 5-HT1B receptor. These interactions between the serotonin system and 17 beta oestradiol may contribute to the increased risk of PAH associated with female gender.