Varying Efficacy of Tadalafil in Bone Morphogenetic Protein Receptor 2 Mutation Carriers Compared to Wild Type Rats in an Experimental Model of Pulmonary Arterial Hypertension
Abstract
Abstract Pulmonary arterial hypertension (PAH) is a rare form of PH, characterized by the endothelial dysfunction with excessive vasoconstriction, as well as remodelling of the pulmonary arterioles ensues, leading to a raise in the pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) and right heart failure. Mutations in the gene for bone morphogenetic protein receptor type II (BMPR2) are causally linked to PAH and account for approximately 75% of familial PAH and up to 25% of sporadic PAH cases. We examined the hypothesis that rats with BMPR2 mutation exhibited greater severity after experimental PAH induction compared to wild type rats and had a diminished response to pharmacological treatment. We generated BMPR2Δex4 heterozygous mutant Sprague-Dawley rats using the CRISPR/Cas9 method by adding a stop codon in exon 1, leading to a truncated protein. We observed that BMPR2Δex4 rats did not naturally develop pulmonary vascular pathology in their first year without being induced with Sugen5416 (20 mg/kg) and three weeks of chronic hypoxia. Twenty-four hours after returning to normoxia, ultrasound analysis (Vevo3100 Fujifilm-Visualsonics) was used to assess PAH establishment and rats were randomized to receive Tadalafil (20 mg/kg, p.o., q.d.) or vehicle for 21 days. At the end, echocardiographic parameters (pulmonary artery acceleration time, PAAT; right ventricle wall thickness, RVWT; stroke volume, SV; cardiac output, CO) were recorded before…
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