An investigation of the origins of pulmonary artery lesion cells in pulmonary arterial hypertension rat models

Aims: To evaluate the origin of the intractable vascular lesions in pulmonary arterial hypertension (PAH) rat models by using bone marrow (BM) and orthotopic lung transplantation (LT). Methods: Chimeric rats in which BM cells were replaced with green fluorescent protein (GFP) positive cells were treated with Sugen (SU)5416 and chronic hypoxia (chimeric Su/Hx). For LT with Su/Hx (LT + Su/Hx), male rats received a left lung from female donors and female rats received one from male donors, followed by Su/Hx treatment. For both chimeric Su/Hx and LT + Su/Hx rats, hemodynamic measurements and immunohistochemistry (IHC) were performed. For chimeric models, the percentage of GFP-positive cells in each lung cell population was evaluated by flow cytometry (FCM). For LT models, fluorescence in situ hybridization (FISH) were done to detect the Y chromosome. Results: Chimeric Su/Hx rats had less severe PAH than their wild-type counterparts and had no plexiform lesions. However, in the chimeric Su/Hx models, the GFP-positive cell ratios of both vascular endothelial cells (ECs) and smooth muscle cells (SMCs) were higher than in chimeric control rats. GFP positive cells were confirmed in vascular lesions by IHC. LT + Su/Hx rats exhibited more severe PAH and plexiform lesions. In male rats that received a left lung from female donors, numerous Y chromosome-positive cells suspected of BM origin were detected in the plexiform lesion of the female donor lung. The Y chromosome-positive cell ratio in ECs and SMCs was similar to the results of FCM in the chimeric Su/Hx rats. Conclusion: BM-derived cells are significantly associated with intractable pulmonary artery lesions.