Metabolic Differences Between Endothelial Cells in PH Phenotypes Explained

This new study aimed to identify metabolic differences in endothelial cells in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (PH) to aid in the development of novel therapeutic approaches.

A new study has compared endothelial cells (ECs) from patients with 2 pulmonary hypertension (PH) phenotypes, pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), to provide insight into the pathophysiology of each.

In all, there are 5 clinical types of PH: PAH, CTEPH, PH associated with lung disease and/or hypoxia, PH with unclear or multifactorial mechanisms, and PH due to left heart disease (the most common subtype). PAH and CTEPH are both characterized by obstructive vasculopathy.

In PAH, endothelial dysfunction and metabolic changes involving increased glycolysis are key aspects of the condition’s pathophysiology. Problematic hyperproliferative, death-resistant cells in PAH are supported by the increased glycolysis.

CTEPH is a severe form of PH in which mean pulmonary arterial pressure (mPAP) rises due to thrombotic lesions in pulmonary arteries that go unresolved despite treatment with anticoagulant therapy. Less is known about ECs in patients with CTEPH.

“To date, exact molecular and metabolic mechanisms, similarities, and divergences between PAH and CTEPH and regulatory pathways behind vascular remodeling and disease progression are not fully resolved,” the study authors wrote in Scientific Reports.

In general, the pulmonary vascular endothelium is key in maintaining homeostasis in blood vessels. EC dysfunction is associated with endothelial stimulation or injury, which can also affect cellular metabolism and pulmonary vascular remodeling. Increased cellular reproduction, angiogenesis, and a phenotype of cells that are pro survival can result from EC metabolic alterations and worsen vascular disease.

The study isolated ECs from the vascular tissue of 18 patients—12 with CTEPH and 6 with PAH—during pulmonary endarterectomy or lung transplantation. All of the patients with PAH and 8 with CTEPH were treated with targeted PAH therapy, and the remaining 4 CTEPH patients did not receive PAH-specific treatment. The EC cells were assessed with a quantitative polymerase chain reaction assay to measure mRNA levels of metabolic genes.

ECs from patients with CTEPH (CTEPH-ECs) and those from patients with PAH (PAH-ECs) showed differing reliance on glycolysis, with PAH-ECs showing higher expression of enzymes that are glycolytic and higher levels of oxidative phosphorylation complexes. In addition, glutamine metabolism, which is potentially involved in PAH pathology, was altered in the CTEPH-ECs in this study.

“Accordingly, a substantially different metabolic profile at the level of glycolysis, oxidative phosphorylation, and glutamine metabolism is present in PAH-ECs compared to CTEPH-ECs and suggests differences in molecular mechanisms and regulatory pathways that could be important in the disease pathology and treatment,” the authors wrote.

Compared with healthy cells and with PAH-ECs, CTEPH-ECs appear to be associated with metabolic impingements that may involve lower glycolysis and glutaminolysis. Given that this study found upregulation in glycolytic genes in PAH-ECs, the findings regarding CTEPH-ECs suggest different metabolic profiles between these disease subtypes.

The ECs in were treated with the metabolic inhibitors 3PO, DCA, BPTES, and UK-5099 to see whether the differences between the cell metabolisms could affect the cells’ viability after treatment. PAH-ECs were more affected when treated with 3PO, DCA, and BPTES compared with other cells, likely due to the higher glycolytic and glutamine-related enzyme levels in these cells. In CTEPH-ECs, however, blocking glycolysis may not be beneficial.

The authors concluded, “More studies are needed to better understand the importance of reduced glycolysis and glutaminolysis in CTEPH-ECs and whether such differences may lead to the development of novel therapeutic approaches to treat CTEPH.”

Reference

Smolders VFED, Rodríguez C, Blanco I, et al. Metabolic profile in endothelial cells of chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension. Sci Rep. Published online February 10, 2022. doi:10.1038/s41598-022-06238-z