The serotonin transporter, gender, and 17ß oestradiol in the development of pulmonary arterial hypertension.
Cardiovasc Res
; 90(2): 373-82, 2011 May 01.
Article
em En
| MEDLINE
| ID: mdl-21177701
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 ANDRESULTS:
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 17ß oestradiol re-established the PAH phenotype in ovariectomized, normoxic, and hypoxic SERT+ mice. 17ß oestradiol also up-regulated tryptophan hydroxylase-1 (TPH1), 5-hydroytryptamine(1B) (5-HT(1B)) receptor, and SERT expression in human pulmonary arterial smooth muscle cells (hPASMCs). 17ß oestradiol stimulated hPASMC proliferation and this was inhibited by both the TPH inhibitor para-chlorophenylalanine and the 5-HT(1B) receptor antagonist SB224289.CONCLUSION:
17ß oestradiol is critical to the development of PAH and severe hypoxia-induced PAH in female SERT+ mice. In hPASMCs, 17ß oestradiol-induced proliferation is dependant on de novo serotonin synthesis and stimulation of the 5-HT(1B) receptor. These interactions between the serotonin system and 17ß oestradiol may contribute to the increased risk of PAH associated with female gender.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estradiol
/
Proteínas da Membrana Plasmática de Transporte de Serotonina
/
Hipóxia
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Aspecto:
Determinantes_sociais_saude
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Cardiovasc Res
Ano de publicação:
2011
Tipo de documento:
Article