15 February 2020 by Gayathri Viswanathan

Single cell RNA sequencing to guide targeting of G protein-coupled receptors in chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease of the pulmonary vasculature characterized by persistent thrombotic occlusion or stenosis of the pulmonary arteries resulting in pulmonary hypertension (PH). Although pulmonary thromboendarterectomy (PTE) remains the treatment of choice for patients with CTEPH, not all patients will benefit from or receive this highly specialized surgery. Patients whose CTEPH is deemed inoperable are candidates for medical therapy, for which only riociguat, a soluble guanylate cyclase stimulator, is FDA-approved. Other options include off-label use of therapies for pulmonary arterial hypertension (PAH), a related disease of the pulmonary arterioles. Thus, there is a significant unmet need for novel medical therapies for CTEPH. However, specific cell types that are involved in thrombotic lesions are poorly understood. Here, by using insights from single cell RNA sequencing (scRNAseq) of CTEPH thrombus, we uncovered distinct populations of immune cells, phenotypically modulated smooth muscle cells (SMCs) and typical cells of the pulmonary vasculature. Cells derived from CTEPH thrombus have defects in angiogenesis and proliferation. We extended our studies by performing GPCR profiling globally, using data from single cell RNA sequencing (scRNAseq). Global GPCR profiling  allowed us to differentiate receptor expression in different cell types in the myofibroblasts, endothelial cells (ECs) and immune cells that compose the thrombus. Over 50 GPCRs targets have been identified in different cell types in which ~20 GPCRs are expressed in SMCs or ECs. Testing these drug targets in thrombus-derived cells may enable the design of more precisely tailored CTEPH medical therapies. 

About the author

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Gayathri Viswanathan

Postdoctoral Associate

Duke University Medical Center

United States

Key Contributors

Gayathri Viswanathan, Nour Nazo, Ian Cumming, Asvin Ganapathi, Jack Haney, Helene Fradin Kirshner, David Corcoran, Yen-Rei Yu, Sudarshan Rajagopal. Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA. Division of Pulmonary, Department of Medicine, Duke University Medical Center, Durham, NC, USA. Department of Surgery, Duke University Medical Center, Durham, NC, USA. Duke Center for Genomic and Computational Biology, Duke University, Durham, NC, United States of America.

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