Gender Bias in G Protein‐Coupled Receptor Expression in Human Pulmonary Artery Smooth Muscle Cells

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance and proliferation of pulmonary artery smooth muscle cells (PASMC). Female bias of PAH (ratio of 4.1:1, female vs. male) is well known, however not fully understood. G protein‐coupled receptors (GPCRs) are the largest family of receptors and important regulators of PASMC function. Profiling GPCRs in female‐ vs. male‐PASMC could advance the understanding of the disease and highlight the role of novel GPCRs in the female bias of PAH. We used an “unbiased” approach (a TaqMan® GPCR array) to profile GPCR expression in primary human male‐ and female‐PASMC. We found that male‐PASMCs express 190 GPCRs (42 orphan and 148 non‐orphan, n=3), while female‐PASMC express 174 GPCRs (44 orphan and 130 non‐orphan, n=3). GPCR expression correlates with function: for example Gα s ‐coupled GPCRs with formation of cAMP and inhibition of cell proliferation, thus documenting that the GPCR array identifies physiologically relevant GPCRs. We found female‐PASMC have an increased expression of 25 GPCRs (>2‐fold) and a decreased expression (>2‐fold) of 19 GPCRs, compared to male‐PASMCs. Chemokine receptor 1 (CCR1) and the purinergic receptor, P2Y12, both of which are Gα i ­‐coupled, were highly upregulated in female‐PASMC (21‐ and 62‐fold, respectively). GPR75, an orphan GPCR whose expression was also increased in female‐PASMC (confirmed by real‐time PCR), was up‐regulated by 17β‐estradiol in a dose‐dependent manner (0.1 nM‐1 μM, 24 h). Taken together these data provide evidence that GPCR expression in PASMC is gender specific and such differences may contribute to the physiology of normal PASMC and the female bias of PAH. Support or Funding Information ATS foundation and Pulmonary Hypertension Association and University of Aberdeen