The effects of gender on the development of pulmonary arterial hypertension in mice over-expressing the serotonin transporter

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).1There is a wealth of evidence to suggest that serotonin is involved in the pathogenesis of PAH.2 Indeed, we have previously shown that female mice over-expressing the serotonin transporter (SERT+ mice) develop increased pulmonary arterial pressures.3 We now investigate the effects of gender on development of PAH in SERT+ mice under both normoxic and hypoxic (10% O2 for 2 weeks) conditions.

Mice (C57/BL6xCBA, 25-45g, 5 months old) were anaesthetised using isoflurane and right ventricular pressure (RVP) obtained via a needle inserted directly into the right ventricle. Pulmonary vascular remodelling was assessed by calculating the percentage of remodelled pulmonary arteries <80μm i.d. Statistical analysis was by two-way analysis of variance. Data are expressed as mean±s.e.m.

Female SERT+ mice displayed elevated systolic RVP (sRVP; 26.9±1.7mmHg cf 20.2±0.7mmHg, p<0.001) and pulmonary vascular remodelling (11.3±0.6% cf 7.9±0.6%, p<0.05) compared with wildtype controls, whilst male SERT+ mice did not. However, in response to hypoxia male wildtype mice developed exaggerated elevations in sRVP (38.4±2.2mmHg cf 28.5±2.2mmHg, p<0.05) and pulmonary vascular remodelling (24.8±0.6% cf 18.3±1.1%, p<0.05) compared to hypoxic female wildtype mice. Hypoxic female SERT+ mice also displayed elevated sRVP (38.7±3.9mmHg, p<0.05) and pulmonary vascular remodelling (24.7±1.5%, p<0.01) compared to hypoxic female wildtype mice. Hypoxic male SERT+ mice displayed similar levels of sRVP and pulmonary vascular remodelling to hypoxic male wildtype mice.

In conclusion, over-expression of SERT results in the development of PAH in female but not male mice. Paradoxically, however, female mice develop less severe hypoxic-induced PAH than males, unless the SERT gene is over-expressed. These results suggest that interactions between the serotonin system and female gender predispose to the development of PAH in mice. Therefore, SERT+ mice make an appropriate novel model with which to study the effects of gender on the development of PAH.

1. Abenhaim et al., (1996) N. Eng. J. Med. 335: 609-616.
2. Dempsie & MacLean, (2008) Br. J. Pharmacol. 155: 455-462.
3. MacLean et al., (2004) Circulation 109: 2150-2155.