Abstract
Introduction: Pulmonary arterial hypertension (PAH) is an uncurable disease characterized by pulmonary vasoconstriction and remodeling, elevated right ventricle systolic pressure (RVSP), and right ventricle hypertrophy (RVH). Recently, our group showed that BMPR2 +/R899X loss-of-function mutation per se significantly increased vasoconstrictive Endothelin-1 (ET-1) in the lungs of female animals, who also exhibited higher RVSP compared to males. Why females have higher PAH incidence remains unclear. Hypothesis: We hypothesize that higher PAH incidence in female mice carrying the BMPR2 +/R899X mutation is associated with the spontaneous development of pulmonary vascular inflammation and ET-1-mediated vasoconstriction. Methods: To test this hypothesis, we used 12-month-old male and female wild-type and BMPR2 +/R899X mutant mice for quantification of RVSP and RVH and for analysis of the ET-1 and CD45+ pulmonary expression by Western Blot and immunohistochemistry. Results: In opposition to BMPR2 +/R899X mutant animals, data indicated no significant difference between sexes regarding ET-1 expression and RVSP in wild-type animals. When investigating the source of ET-1 in the lungs of BMPR2 +/R899X female mice, our preliminary data suggested it accumulates in perivascular cells. Moreover, double-blind immunohistochemistry examination of the pan-leukocyte marker CD45 revealed a massive perivascular infiltration of CD45+ cells in the lungs of female mutant animals compared to males (4.09 +/- 0.68 and 10.46 +/- 1.15 CD45+ cells/microvessel, male and female, respectively; 8 micrographs/animal; 3 mice/group), supporting our hypothesis that BMPR2 +/R899X mutation is an important factor for sex-linked vascular inflammation in PAH. Conclusion: In conclusion, elevated perivascular CD45+ cells in the lungs of female BMPR2 +/R899X mutant mice may contribute to PAH sex bias.
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