Increased Pyruvate Dehydrogenase Kinase 4 Expression in Lung Pericytes Is Associated with Reduced Endothelial-Pericyte Interactions and Small Vessel Loss in Pulmonary Arterial Hypertension

Abstract

Reduced endothelial-pericyte interactions are linked to progressive small vessel loss in pulmonary arterial hypertension (PAH), but the molecular mechanisms underlying this disease remain poorly understood. To identify relevant gene candidates associated with aberrant pericyte behavior, we performed a transcriptome analysis of patient-derived donor control and PAH lung pericytes followed by functional genomics analysis. Compared with donor control cells, PAH pericytes had significant enrichment of genes involved in various metabolic processes, the top hit being PDK4, a gene coding for an enzyme that suppresses mitochondrial activity in favor of glycolysis. Given reports that link reduced mitochondrial activity with increased PAH cell proliferation, we hypothesized that increased PDK4 is associated with PAH pericyte hyperproliferation and reduced endothelial-pericyte interactions. We found that PDK4 gene and protein expression was significantly elevated in PAH pericytes and correlated with reduced mitochondrial metabolism, higher rates of glycolysis, and hyperproliferation. Importantly, reducing PDK4 levels restored mitochondrial metabolism, reduced cell proliferation, and improved endothelial-pericyte interactions. To our knowledge, this is the first study that documents significant differences in gene expression between human donor control and PAH lung pericytes and the link between mitochondrial dysfunction and aberrant endothelial-pericyte interactions in PAH. Comprehensive characterization of these candidate genes could provide novel therapeutic targets to improve endothelial-pericyte interactions and prevent small vessel loss in PAH.

Metabolic Coordination of Pericyte Phenotypes: Therapeutic Implications

“…On the opposite spectrum, excessive pericyte proliferation promotes disease progression in pulmonary artery hypertension (PAH), hypoxia-induced retinopathies (characterized by excessive neovascularization), and kidney and liver fibrosis (Rabinovitch, 2012;Ferland-McCollough et al, 2017;Dubrac et al, 2018). Studies using pericytes derived from PAH patients indicate that aberrant pericyte proliferation and migration is fueled by glycolysis, as these cells had elevated glycolytic capacity and lower mitochondrial activity (Rabinovitch, 2012;Yuan et al, 2016). Thus, repression of pericyte glycolytic activity could provide a useful therapeutic approach in this disease.…”

“…Thus, repression of pericyte glycolytic activity could provide a useful therapeutic approach in this disease. Recently, siRNA-mediated knock-down of PDK4 (which suppresses mitochondrial activity in favor of glycolysis by inhibition of pyruvate dehydrogenase) was shown to increase PAH-derived pericyte mitochondrial function, lower their proliferation and improve their interactions with endothelial cells (Yuan et al, 2016), demonstrating promise of this conceptual approach. Similar strategies may be useful in regulating pericyte proliferation in chronic kidney disease or retinopathies, although these approaches remain to be tested.…”

Metabolism within the tumor microenvironment and its implication on cancer progression: An ongoing therapeutic target

“…Several studies have been carried out in retinal pericytes in the context of diabetic retinopathy, but without exploring glucose metabolism in pericytes . The only work about pericyte metabolism performed to our knowledge demonstrated that lung pericytes from pulmonary arterial hypertension patients presented higher expression of PDK‐1, an inhibitor of PDH, than healthy pericytes . Therefore, it could be considered that normal pericytes display higher rates of OXPHOS than those of glycolysis.…”

Hypertension Induced Morphological and Physiological Changes in Cells of the Arterial Wall

“…54,58,59 Hypertension has been associated with both an increase and a decrease in pericyte numbers. [60][61][62][63][64] In mice with Ang-II-induced hypertension, the number of pericytes in cerebral arteries is decreased, leading to blood-brain barrier disruption. 60 In contrast, SHR show increased pericyte number within the brain microcirculation, specifically within the motor cortex and pons.…”