Abstract 148: Blockade of the Serotonin 2B Receptor Prevents Pulmonary Vascular Stiffening and Remodeling in a Mouse Model of Familial Pulmonary Arterial Hypertension

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Objective: Pulmonary arterial hypertension (PAH) is a fatal disease of the pulmonary vasculature. In humans, familial PAH is caused by mutations in the bone morphogenetic protein receptor 2 gene (BMPR2). Serotonin signaling through the 2B receptor (5HT2BR) is also important in the pathogenesis of PAH, making 5HT2BR antagonism a potential target for PAH therapeutics. This study evaluates the hypothesis that antagonism of 5HT2BR will prevent PAH in a genetic mouse model and the pulmonary vascular stiffening and remodeling that is considered the underlying cause. Methods: Rosa26-Bmpr2 R899X mice on an FVB/N background express the patient-derived R899X mutation in BMPR2 in all tissues when induced with doxycycline. 10-14 week old BMPR2 mutant mice were fed doxycycline in a high-fat diet for 6 weeks. After 2 weeks, osmotic pumps containing either the 5HT2BR antagonist SB204741 (1 mg/kg/day) or DMSO/water vehicle were implanted. Right ventricular systolic pressure (RVSP) was measured via a venous jugular catheter under anesthesia, and the mice euthanized. Lungs were collected and prepared for histology, gene expression analysis, and atomic force microscopy (AFM, Bioscope Catalyst). Immortalized pulmonary microvascular smooth muscle cells (SMCs) with a BMPR2 mutation were assessed for long-term changes in cytoskeletal contractility using a free floating collagen gel assay. Data: BMPR2 R899X mice treated with SB204741 failed to develop elevated RVSP. Histologic analysis revealed that SB204741 reduced both the total number of inflammatory cells in the lung as well as the muscularization of peripheral pulmonary arterioles. Microarray analysis revealed that 5HT2BR antagonism primarily changed the expression contractility-associated genes. Measurements of pulmonary arteriole elastic modulus with AFM show significantly increased vessel wall stiffness in BMPR2 R899X arterioles that is also normalized with SB204741 treatment. Taken together, these data suggest that 5HT2BR antagonism prevents the vascular stiffening and remodeling that causes PAH.