G protein-coupled receptor expression and function in pulmonary artery smooth muscle cells: new targets in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, in part due to increased proliferation of pulmonary artery smooth muscle cells (PASMC). Since 3’5’-cyclic adenosine monophosphate (cAMP) decreases proliferation of PASMC, G protein-coupled receptors (GPCRs) that couple to Gαs or Gαi are attractive targets for the treatment of PAH. We used a real-time PCR GPCR array to identify and quantify the GPCRs expressed by PASMC isolated from normal subjects and from patients with PAH. We found that human PASMC express >135 GPCRs, at least 60 of which regulate cAMP formation. GPCR expression correlates with function: for Gαs-coupled GPCRs with formation of cAMP and inhibition of cell proliferation, thus documenting that the GPCR array identifies physiologically relevant GPCRs. PAH-PASMC (both from idiopathic and secondary PAH patients) have an increase (>2-fold) in the expression of 41 GPCRs compared to control-PASMC, including multiple GPCRs that link to Gαs or Gαi. In addition, PAH-PASMC have a higher expression of GPCRs that preferentially couple to Gαq/11 or to Gα12/13. Taken together these data provide evidence that a GPCRomic approach can identify GPCRs that may contribute to the physiology of PASMC and that may be new druggable targets for PAH, a disease for which no currently optimal therapies exist.