Global and Endothelial G-Protein Coupled Receptor 75 (GPR75) Knockout Relaxes Pulmonary Artery and Mitigates Hypoxia-Induced Pulmonary Hypertension

Authors

Catherine A. D'Addario, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Shun Matsumura, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.Follow
Atsushi Kitagawa, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Gregg M. Lainer, Department of Cardiology, and Heart and Vascular Institute, Westchester Medical Center and New York Medical College, Valhalla, NY 10595, USA.
Frank Zhang, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.Follow
Melinee D'silva, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Mohammad Y. Khan, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Ghezal Froogh, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Artiom Gruzdev, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Darryl C. Zeldin, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Michal L. Schwartzman, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.Follow
Sachin A. Gupte, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA. Electronic address: s_gupte@nymc.edu.Follow

Author Type(s)

Faculty

DOI

https://doi.org/10.1016/j.vph.2023.107235

Journal Title

Vascular Pharmacology

First Page

107235

Document Type

Article

Publication Date

12-1-2023

Department

Medicine

Second Department

Pharmacology

Abstract

RATIONALE: Pulmonary hypertension (PH) is a multifactorial disease with a poor prognosis and inadequate treatment options. We found two-fold higher expression of the orphan G-Protein Coupled Receptor 75 (GPR75) in leukocytes and pulmonary arterial smooth muscle cells from idiopathic PH patients and from lungs of C57BL/6 mice exposed to hypoxia. We therefore postulated that GPR75 signaling is critical to the pathogenesis of PH. METHODS: To test this hypothesis, we exposed global (Gpr75) and endothelial cell (EC) GPR75 knockout (EC-Gpr75) mice and wild-type (control) mice to hypoxia (10% oxygen) or normal atmospheric oxygen for 5 weeks. We then recorded echocardiograms and performed right heart catheterizations. RESULTS: Chronic hypoxia increased right ventricular systolic and diastolic pressures in wild-type mice but not Gpr75 or EC-Gpr75 mice. In situ hybridization and qPCR results revealed that Gpr75 expression was increased in the alveoli, airways and pulmonary arteries of mice exposed to hypoxia. In addition, levels of chemokine (CC motif) ligand 5 (CCL5), a low affinity ligand of GPR75, were increased in the lungs of wild-type, but not Gpr75, mice exposed to hypoxia, and CCL5 enhanced hypoxia-induced contraction of intra-lobar pulmonary arteries in a GPR75-dependent manner. Gpr75 knockout also increased pulmonary cAMP levels and decreased contraction of intra-lobar pulmonary arteries evoked by endothelin-1 or U46619 in cAMP-protein kinase A-dependent manner. CONCLUSION: These results suggest GPR75 has a significant role in the development of hypoxia-induced PH.

Recommended Citation

D'Addario, C. A., Matsumura, S., Kitagawa, A., Lainer, G. M., Zhang, F., D'silva, M., Khan, M. Y., Froogh, G., Gruzdev, A., Zeldin, D. C., Schwartzman, M. L., & Gupte, S. A. (2023). Global and Endothelial G-Protein Coupled Receptor 75 (GPR75) Knockout Relaxes Pulmonary Artery and Mitigates Hypoxia-Induced Pulmonary Hypertension. Vascular Pharmacology, 153, 107235. https://doi.org/https://doi.org/10.1016/j.vph.2023.107235