The effects of endogenous oestrogen on the development of PAH in mice over-expressing the serotonin transporter

Kevin White, Yvonne Dempsie, Margaret Nilsen, Lynn Loughlin, Margaret R MacLean. University of Glasgow, Glasgow, United Kingdom.

Pulmonary arterial hypertension (PAH), in its idiopathic and familial forms, occurs more commonly in women than in men (>2:1).1 We have previously shown that whilst female mice over-expressing the serotonin transporter (SERT+ mice) develop PAH, male SERT+ mice do not. Therefore we hypothesised that an interaction between oestrogen and over-activity of the serotonin system may lead to the development of PAH. We now investigate the role of endogenous oestrogen in the development of PAH in SERT+ mice under both normoxic and hypoxic conditions.

Female mice (C57/BL6xCBA, 15-20g, 8-10 weeks old) were ovariectomised or sham operated. Ten weeks after the procedure, mice were exposed to 2 weeks of hypobaric hypoxia (10% O2), whilst control mice were kept in normoxia. Mice were then anaesthetised using isoflurane and right ventricular pressure (RVP) obtained via a needle inserted directly into the right ventricle. Right ventricular hypertrophy (RVH) was assessed by measuring the weight ratio of the right ventricular free wall (RV) to that of the left ventricle together with the septum (LV + S). Statistical analysis was by two-way analysis of variance. Data are expressed as mean±s.e.m.

Ovariectomy increased systolic RVP (sRVP) in normoxic wildtype mice (25.96±0.79mmHg cf 20.65±0.58mmHg, p<0.01), but had no effect on sRVP in normoxic SERT+ mice. Under hypoxic conditions ovariectomy had no effect on sRVP in wildtype mice, but reduced the exaggerated increase in sRVP observed in SERT+ mice (31.86±2.00mmHg cf 40.77±2.70mmHg, p<0.05). Ovariectomy had no effect on RVH in either normoxic wildtype or SERT+ mice. However, under hypoxic conditions, ovariectomy increased RVH in wildtype mice (0.346±0.010 cf 0.290±0.008, p<0.01), whilst having no effect on SERT+ mice.

Our results suggest that endogenous oestrogen may lower sRVP under normal conditions. In addition, endogenous oestrogen may have a protective effect on hypoxia-induced RVH in wildtype animals. However, in the presence of a combination of risk factors for PAH, ie hypoxia and over-expression of the SERT, endogenous oestrogen may lose its protective role and paradoxically exacerbate increases in RVP. In conclusion, female gender may interact with various risk factors to play a permissive role in the development of PAH.

1. Abenhaim et al., (1996) N. Eng. J. Med. 335: 609-616.