Consequence of Desmin gene mutation on development of chronic hypoxic pulmonary hypertension in mice

Introduction Desmin deficiency is responsible for various forms of skeletal and cardiac disorders. However, role of desmin in the normal and pathological pulmonary vasculature remains unknown. Objective To investigate whether desmin deficiency affects pulmonary circulation in normoxic and hypoxic conditions. Methods Desmin-deficient mice (Des-/-) and their littermate Des+/+ (controls) aged 2–4 months were exposed to chronic hypoxia (9% O2, 2 weeks) or normoxia. Cardiac function was assessed by closed-chest echocardiography and right ventricle (RV) hemodynamics combined with measurements of Fulton Index and muscularization of pulmonary arteries (PA). Contractile properties of intrapulmonary arteries were measured by using an arteriography. Heart and lung phenotype were determined by using standard techniques of histology, immunostaining, immunoblot and RT-qPCR analysis. Results Under normal conditions Des-/- mice developed cardiomyopathy with alteration of both left ventricle (LV) and RV functions. Left Heart Disease was characterized by ventricular dilatation, decreased Ejection Fraction and Strain Rate in agreement with extreme transmural fibrosis and cardiomyocytes hypertrophy. RV dysfunction was evidenced by an increase of RV systolic pressure (RVSP) and PA muscularization. After exposure to hypoxia, LV function was globally not modified in both Des-/- and Des+/+ mice. RV was similarly affected in both strains, though the increase of RV weight, RVSP and PA muscularization were higher in Des-/- mice. Conversely, contractile capacities of PA were not modified in Des-/- mice in normoxia. Under hypoxia, we recorded modifications of several contractile, structural and Ca2 ± handling proteins in PA - smooth muscle cells (SMC). Conclusion Our results indicate that desmin can be replaced by vimentin in SMC without loss of function. However, clinical features of desminopathies can also include pulmonary hypertension with PA remodeling and higher RV dysfunction.