Vascular remodelling is reversed following BMPR2 modified endothelial progenitor cell therapy in a MCT-induced PAH rat model

Abstract

Introduction: Pulmonary arterial hypertension (PAH) is caused by pulmonary vascular remodelling. Reduced expression of the bone morphogenetic protein receptor type-2 (BMPR2) is causally linked to PAH. Previously, we have augmented endothelial progenitor cells (EPCs) to over-express BMPR2 and transplanted them in a monocrotaline (MCT)-induced PAH rat model resulting in an amelioration of the disease. We now assess the effects of our BMPR2-EPC and EPC only therapy on vascular remodelling in this MCT-induced PAH rat model. Method: Rats (n=8) were injected with MCT, and then at day 10, rats were intravenously injected with EPCs only, AdBMPR2 transfected EPCs, or uninjected. After a further 8-10 days, PAH was assessed and lungs were extracted and processed into paraffin blocs. Immunohistochemical analysis on vessels 50µm or less was performed with α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA). Results: After 8-10 days PAH was shown to be attenuated in the BMPR2-transduced EPC group, with a reduction in the mPAP of the EPCs Only group compared to MCT Only. Rats treated with EPCs Only had a significant reduction by 30.47% in vessel muscularisation and 39.59% reduction in cellular proliferation compared to MCT Only. Rats treated with BMPR2-EPCs had a 31.21% reduction in vessel muscularisation and a 52.97% reduction in cellular proliferation compared to MCT Only treated rats. Discussion: Amelioration of PAH can be achieved using BMPR2 modified EPCs. There9s a significant reduction in distal vessel muscularisation and cellular proliferation following EPCs and BMPR2-EPCs treatment, with a greater effect seen in the BMPR2-EPCs group.