Interactions between the serotonin system and female gender in the development of pulmonary arterial hypertension in mice

Yvonne Dempsie, Margaret Nilsen, Lynn Loughlin, Margaret MacLean

Glasgow University, Glasgow, UK

Pulmonary arterial hypertension (PAH) is a disease associated with both constriction and remodelling of the pulmonary vasculature, eventually leading to right heart failure and death. In its idiopathic and familial forms, it occurs more commonly in women than in men (>2:1) (Abenhaim et al., 1996). There is a wealth of evidence to suggest that serotonin is involved in the pathogenesis of PAH (Dempsie & MacLean, 2008). Indeed, we have previously shown that female mice over-expressing the serotonin transporter (SERT+ mice) develop increased pulmonary arterial pressures (MacLean et al., 2004). 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 (3% for induction and 1-1.5% for maintenance) 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±SEM.

Female SERT+ mice displayed elevated systolic RVP (sRVP) compared with wildtype controls (26.9±1.7mmHg, n=9 cf 20.2±0.7mmHg, n=8, p<0.001), whilst male SERT+ mice did not (20.2±0.5mmHg, n=7 cf 22.9±0.8mmHg, n=8, p>0.05). Female SERT+ mice also exhibited increased pulmonary vascular remodelling (11.3±0.6%, n=5 cf 7.9±0.6%, n=4, p<0.05) whilst male SERT+ mice did not (8.2±1.2%, n=4 cf 8.7±0.8%, n=4, p>0.05). However, in response to hypoxia male wildtype mice developed exaggerated elevations in sRVP (38.4±2.2mmHg, n=6 cf 28.5±2.2mmHg, n=5, p<0.05) and pulmonary vascular remodelling (24.7±1.5%, n=10 cf 18.3±1.1%, n=10, p<0.05) compared to hypoxic female wildtype mice. Hypoxic female SERT+ mice also displayed elevated sRVP (38.7±3.9mmHg, n=6, p<0.05) and pulmonary vascular remodelling (24.7±1.5%, n=10, p<0.01) compared to hypoxic female wildtype mice. Hypoxic male SERT+ mice displayed similar levels of sRVP (39.20±1.5, n=8) and pulmonary vascular remodelling (24.5±0.6%, n=4) 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. As the reason for the prevalence of PAH in female humans is still unclear, SERT+ mice make an appropriate novel model with which to study the effects of gender on the development of PAH.

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