Perivascular macrophages are well documented in patients and animal modelsof pulmonary arterial hypertension (PAH). The exact role for macrophages, and whether their presence or absence is required for the vascular remodelling seen in PAH is unclear. Using a novel inducible macrophage (CD68) depletion model (MacLow) we aimed to determine the requirement for macrophagesin pulmonary arterial remodeling associated with PAH.Following macrophage depletion (~50% of F4/80 postive cells) for 6 weeks’ mice were phenotyped for PAH by echocardiography, closed chest cardiac catheterization and immunohistochemistry (IHC). To investigate the origin of the effector cells, male chimeric mice were generated, and to study gender-specificity of the disease phenotype, mixed gender chimericMacLow/wild type (wt) mice also produced.
Male but not female MacLow mice developed a PAH phenotype compared to controls (RVSP 66 vs 24 mmHg, p< 0.0001, n=5-8), that was associated with right ventricular Hypertrophy (RVH) and pulmonary vascular remodelling. IHC analysis of demonstrated increased iNOS- |CD206+ |F4/80+ macrophages suggesting a M2-like macrophage population drive the PAH phenotype in these mice. Studies on mixed gender chimeric mice demonstrated that neither male or female MacLow BM transferred into wild-type was sufficient to induce PAH, and female MacLow BM failed to protect male MacLow mice suggesting that in a male gender specific manner, resident lung M2-like macrophages drive the development of disease in this model. Studies are currently underway to determine whether 17 beta-oestradiol treatment can prevent development of PAH in male MacLow mice.