Deletion Of G‐Protein‐Coupled Receptor 75 Prevents Hypoxia‐Induced Pulmonary Vasoconstriction and Hypertension

Abstract

Pulmonary Hypertension (PH) is a cardiopulmonary disease estimated to affect between 20 million to 70 million individuals globally, with poor prognosis and inadequate treatment. Recent studies showed the orphan G Protein Coupled Receptor 75 (GPR75) is upregulated in the pulmonary vessels of PH patients, especially in females. Therefore, we hypothesized that Gpr75knock out (Gpr75KO) mice will be protected from developing PH. To test our hypothesis, first we determined the vasoreactivity of isolated intra‐lobar pulmonary arteries from wild‐type (WT) and GPR75KO mice induced by KCl (WT=6; Gpr75KO=8), U46619 (WT=8; Gpr75KO=8), ZD7288 (WT=7; Gpr75KO=7), and Endothelin (WT=7; Gpr75KO=8) to test their vasoreactivity. The Gpr75KO as compared with wild‐type pulmonary arteries contracted less to all the contractile agents. Next, we determine if Gpr75KO mice were protected from developing hypoxia‐induced PH. We placed 3‐month‐old female Gpr75KO (n=8) and control wild‐type (C57BL/C) mice (n=18) in a hypoxic chamber with 10% Oxygen or at atmospheric oxygen for 5 weeks. At the end of 5 weeks, we performed right heart catheterizations. Gpr75KO mice developed less (P<0.05) right ventricle systolic pressure (RVSP: 24.3±1.2 mmHg) and right ventricle diastolic pressure (RVDP: 2.0±0.0 mmHg) than the wild‐type mice under hypoxia (RSVP and RDVP of 56.6±3.5 mmHg and 9.8±0.9 mmHg, respectively). Since GPR75 is a G‐protein coupled receptor to determine secondary messengers that potentially contribute to regulating contractile function of pulmonary arteries, we measured cAMP and IP3 in lungs of wild‐type and GPR75KO mice. While we found no difference in the IP3 levels between the WT and Gpr75KO groups, cAMP levels were significantly higher in Gpr75KO compared to WT mice. These results suggest GPR75 plays a major role in the development of PH by potentially attenuating cAMP‐dependent signaling and concomitantly augmenting pulmonary constriction in response to hypoxia.