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G Protein‐Coupled Receptor (GPCR) Expression in Pulmonary Artery Smooth Muscle Cells of Human and Experimental Models of Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) occurs as a primary (idiopathic) disease (IPAH) and secondary to various conditions. Both types are characterized by increased pulmonary vascular resistance and remodeling of the pulmonary artery, which derives in part from the proliferation of pulmonary artery smooth muscle cells (PASMCs), and can lead to right ventricular (RV) heart failure. Current treatments for PAH are inadequate, especially in terms of impact on mortality; thus, new therapies are needed. Animal models that mimic features of human PAH have been used to assess pathophysiology and evaluate treatments for PAH and include the exposure of rodents to chronic hypoxia (in the absence or presence of the VEGFR inhibitor SU5416) or treatment of rats with monocrotaline. Our studies are testing the hypothesis that previously unrecognized G protein‐coupled receptors (GPCRs) may contribute to PAH pathophysiology and may be new therapeutic targets. To begin to test this hypothesis, we used TaqMan® GPCR arrays as an unbiased approach to identify and quantify GPCRs in PASMCs of humans, rats and mice, including from patients with PAH and experimental PAH animal models. Development of PAH and RV hypertrophy in the animal models was confirmed by immunostaining/histology and quantified using the Fulton index (the [right ventricle]/[left ventricle + septum] weight). We found that PASMCs express >100 GPCRs and that the GPCR expression profiles of mouse and rat PASMCs are similar to that of human PASMCs. Moreover, we find numerous changes (of at least 2‐fold) in GPCR expression of PASMCs from PAH patients compared to control PASMCs. GPCRs with altered expression include receptors that link to G proteins whose signaling effectors (e.g., cAMP, Ca++, etc.) are predicted to regulate PASMC proliferation and tone. These results show that PASMCs express many more GPCRs than previously known and that the GPCR expression profile differs in PAH‐PASMCs. GPCRs with altered expression may contribute to altered function in PAH and thus may be novel therapeutic targets for this disease.