Dataset Information

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.

SUBMITTER: Yuan K

PROVIDER: S-EPMC5012507 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Yuan Ke K Shao Ning-Yi NY Hennigs Jan K JK Discipulo Marielle M Orcholski Mark E ME Shamskhou Elya E Richter Alice A Hu Xinqian X Wu Joseph C JC de Jesus Perez Vinicio A VA

The American journal of pathology 20160725 9

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 ...[more]

PMID: 27456128

Similar Datasets

Project description:BackgroundPulmonary arterial hypertension (PAH) is a life-threatening disorder of the pulmonary circulation associated with loss and impaired regeneration of microvessels. Reduced pericyte coverage of pulmonary microvessels is a pathological feature of PAH and is caused partly by the inability of pericytes to respond to signaling cues from neighboring pulmonary microvascular endothelial cells (PMVECs). We have shown that activation of the Wnt/planar cell polarity pathway is required for pericyte recruitment, but whether production and release of specific Wnt ligands by PMVECs are responsible for Wnt/planar cell polarity activation in pericytes is unknown.MethodsIsolation of pericytes and PMVECs from healthy donor and PAH lungs was carried out with 3G5 or CD31 antibody-conjugated magnetic beads. Wnt expression profile of PMVECs was documented via quantitative polymerase chain reaction with a Wnt primer library. Exosome purification from PMVEC media was carried out with the ExoTIC device. Hemodynamic profile, right ventricular function, and pulmonary vascular morphometry were obtained in a conditional endothelium-specific Wnt5a knockout ( Wnt5aECKO) mouse model under normoxia, chronic hypoxia, and hypoxia recovery.ResultsQuantification of Wnt ligand expression in healthy PMVECs cocultured with pericytes demonstrated a 35-fold increase in Wnt5a, a known Wnt/planar cell polarity ligand. This Wnt5a spike was not seen in PAH PMVECs, which correlated with an inability to recruit pericytes in Matrigel coculture assays. Exosomes purified from media demonstrated an increase in Wnt5a content when healthy PMVECs were cocultured with pericytes, a finding that was not observed in exosomes of PAH PMVECs. Furthermore, the addition of either recombinant Wnt5a or purified healthy PMVEC exosomes increased pericyte recruitment to PAH PMVECs in coculture studies. Although no differences were noted in normoxia and chronic hypoxia, Wnt5aECKO mice demonstrated persistent pulmonary hypertension and right ventricular failure 4 weeks after recovery from chronic hypoxia, which correlated with significant reduction, muscularization, and decreased pericyte coverage of microvessels.ConclusionsWe identify Wnt5a as a key mediator for the establishment of pulmonary endothelium-pericyte interactions, and its loss could contribute to PAH by reducing the viability of newly formed vessels. We speculate that therapies that mimic or restore Wnt5a production could help prevent loss of small vessels in PAH.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets