Asthma associated vascular endothelial dysfunction and the role of sex hormones in ovariectomized and castrated C57/BL6 mice

Abstract ID 87562 Poster Board 063 Background: Asthma is a complex airway inflammatory disorder that affects people of all ages, sexes, races, and ethnicities. Interestingly, asthma is more likely to occur in prepubescent males than females, however, this sex specific incidence of asthma reverses after puberty. In addition, recent clinical evidence suggests that adult females develop severe asthma that is associated with an increased risk of cardiovascular disease (CVD). Despite this sex disparity in asthma and CVD events in clinical observations, the pathophysiological mechanisms by which asthma, sex, and CVD interact are still poorly understood. Objectives: The purpose of this study was to compare sex differences in asthma related vascular dysfunction, and to gain insight into the role of sex hormones in asthma related vascular and lung inflammation. Methods: C57/BL6 mice were randomly assigned into eight groups: 1) sham female vehicle control (VC), 2) ovariectmized (OVX) VC, 3) sham female asthma, 4) OVX asthma, 5) sham male VC, 6) castrated (CAST) male VC, 7) sham male asthma, 8) CAST asthma. Experimental asthma was induced by ovalbumin sensitization (i.p. injection 20ug), followed by 5% ovalbumin aerosol challenges for 2 weeks. Airway inflammation was determined by bronchoalveolar lavage (BAL), and vascular reactivity was measured by isometric tension experiments. Results: In the female groups, both asthmatic groups developed pulmonary eosinophilia and the BAL fluid eosinophil percentage was significantly higher in OVX asthma mice (Sham asthma: 58 ± 9 vs. OVX asthma 76 ± 5 %, p < 0.05). Acetylcholine (Ach) induced maximal aortic relaxation was reduced in both asthmatic groups (Sham VC: 83 ± 4, OVX VC: 86 ± 2, Sham asthma: 63 ± 5, and OVX asthma: 59 ± 8 %, p < 0.05), but there were no differences between the Sham and OXX asthmatic groups. In control animals, Ach induced relaxation was mainly mediated by nitric oxide (NO). Conversely, in both sham and OVX asthmatic groups, large Ach-induced relaxation (20%) was observed in the presence of L-NAME and indomethacin (Indo). In the male groups, the BAL fluid eosinophil percentage was higher in asthmatic mice, but there were no differences between sham and CAST asthmatic groups. Maximal relaxation responses to Ach were reduced in both asthmatic groups, but there were no differences between sham and CAST asthma groups. (VC: 86 ± 2, OVX VC: 86 ± 4, Sham asthma: 68 ± 4, and OVX asthma: 68 ± 4 %, p< 0.05). Similar to the females, male asthmatic mice showed L-NAME and Indo resistant relaxation (30%). Conclusions: Our data suggest the possibility that a lack of female sex hormones may be an important mechanism underlying the severity of lung allergic responses, but the magnitude of aortic endothelial dysfunction appears to be similar in all asthmatic groups. Also, NO and prostacyclin cannot entirely account for endothelial dependent dilation of the aorta in asthmatic mice, suggesting increased endothelium-derived hyperpolarizing factors. Further investigation is required to find a potential link between lung and vascular inflammation in asthma. Supported by the West Virginia IDEA Network of Biomedical Research Excellence (5P20GM103434).