Fellows publications

Is PAH a gender biased disease? The role of S100A4/Mts1 in developing PAH is specific to female mice

Pulmonary arterial hypertension (PAH) is a debilitating disease associated with increased constriction and remodeling of the pulmonary vasculature.  Patients are diagnosed with PAH when they have a mean pulmonary arterial pressure greater than 25 mm Hg at rest, or greater than 30 mm Hg during exercise.   There are several etiologies of PAH, including idiopathic PAH (iPAH), heritable PAH (hPAH), or PAH associated with connective tissue disease, congenital left-to-right shunt, hemoglobinopathies, HIV disease, schistosomiasis, and liver disease.

Of the various etiologies, iPAH and hPAH are more prevalent in women than in men (>2:1) for reasons that remain to be elucidated.  Investigating gender differences and the molecular mechanisms that sex hormones have in PAH in vivo is difficult, and animal models have been criticized for not adequately representing human disease.  The two most commonly used rodent models are chronic exposure to hypoxia, which produces moderate irreversible PH, and exposure to monocrotaline, a plant alkaloid that causes pulmonary hypertension through extensive inflammatory lesions in the vasculature.  Gender differences have been noted to cause differences in responsiveness to experimental pulmonary hypertension in animal models.  For instance, male rats are more susceptible to developing hypoxia-induced pulmonary hypertension than female rats, and estrogen, ironically protects against monocrotaline-induced pulmonary hypertension. 

Dempsie et al. (2011) 1 demonstrate that the Mts1/RAGE pathway may play a role in the gender bias associated with pulmonary arterial hypertension.  For instance, they show that in Mts1+ mice, the female gender is more vulnerable to developing PAH, as well as developing plexiform-like lesions, when compared to male Mts1+ mice, which is consistent with earlier findings that Mts1 is up-regulated in the neointima and adventitia of occlusive and early plexiform lesions in PAH patients.   Moreover, they show that in female mice, there is greater Mts1 expression in the distal pulmonary arteries and that physiological concentrations of 17b-estradiol can increase proliferation of the distal PASMCs, which can be a possible explanation as to why PAH is more profound in the female gender.  Mts1+ mice show an increase in both systolic right ventricular pressure as well as remodeling of the pulmonary vasculature, which is consistent with the classical hemodynamic and physiologic characterization of PAH in both humans and experimental models.  This finding is also indicative that Mts1 may be a modulator remodeling of the pulmonary vasculature.  Since it is well established that Mts1 works via RAGE, they aimed to investigate whether there was variability in expression of RAGE based on gender, and found that there were no differences in expression levels in the lung of male vs. female, however there was a minor increase in RAGE expression in the pulmonary artery in females, as shown by immunohistochemistry, respectively.

In Conclusion, Dempsie et al. (2011)  demonstrated that the female gender is more permissive in developing PAH in Mts1+ mice, and that 17b-estradiol can up-regulate Mts1 expression and also induce hPASMC proliferation upon activation of RAGE.  Thus, the activation of 17b-estradiol/Mts1/Rage pathway may contribute to gender bias associated with pulmonary arterial hypertension. 

• 1. Demspie Y, Nilsen M, White K, Mair KM, Loughlin L, Ambartsumian N, Rabinovitch M, MacLean MR. Development of pulmonary arterial hypertension in mice over-expressing S100A4/Mts1 is specific to females. Respiratory Research 2011; 12:159.