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Increased Lymphangiogenesis and Lymphangiogenic Growth Factor Expression in Perivascular Adipose Tissue of Patients with Coronary Artery Disease.

ABSTRACT: Experimental and human autopsy studies have associated adventitial lymphangiogenesis with atherosclerosis. An analysis of perivascular lymphangiogenesis in patients with coronary artery disease is lacking. Here, we examined lymphangiogenesis and its potential regulators in perivascular adipose tissue (PVAT) surrounding the heart (C-PVAT) and compared it with PVAT of the internal mammary artery (IMA-PVAT). Forty-six patients undergoing coronary artery bypass graft surgery were included. Perioperatively collected C-PVAT and IMA-PVAT were analyzed using histology, immunohistochemistry, real time PCR, and PVAT-conditioned medium using cytokine arrays. C-PVAT exhibited increased PECAM-1 (platelet endothelial cell adhesion molecule 1)-positive vessel density. The number of lymphatic vessels expressing lymphatic vessel endothelial hyaluronan receptor-1 or podoplanin was also elevated in C-PVAT and associated with higher inflammatory cell numbers, increased intercellular adhesion molecule 1 (ICAM1) expression, and fibrosis. Significantly higher expression of regulators of lymphangiogenesis such as vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor-3 was observed in C-PVAT compared to IMA-PVAT. Cytokine arrays identified angiopoietin-2 as more highly expressed in C-PVAT vs. IMA-PVAT. Findings were confirmed histologically and at the mRNA level. Stimulation of human lymphatic endothelial cells with recombinant angiopoietin-2 in combination with VEGF-C enhanced sprout formation. Our study shows that PVAT surrounding atherosclerotic arteries exhibits more extensive lymphangiogenesis, inflammation, and fibrosis compared to PVAT surrounding a non-diseased vessel, possibly due to local angiopoietin-2, VEGF-C, and VEGF-D overexpression.

SUBMITTER: Drosos I

PROVIDER: S-EPMC6678243 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Increased Lymphangiogenesis and Lymphangiogenic Growth Factor Expression in Perivascular Adipose Tissue of Patients with Coronary Artery Disease.

Drosos Ioannis I Pavlaki Maria M Ortega Carrillo Maria Del Pilar MDP Kourkouli Adriani A Buschmann Katja K Konstantinou Fotios F Gogiraju Rajinikanth R Bochenek Magdalena L ML Chalikias Georgios G Tortopidis Christos C Vahl Christian F CF Mikroulis Dimitrios D Tziakas Dimitrios D Münzel Thomas T Konstantinides Stavros S Schäfer Katrin K

Journal of clinical medicine 20190709 7

Experimental and human autopsy studies have associated adventitial lymphangiogenesis with atherosclerosis. An analysis of perivascular lymphangiogenesis in patients with coronary artery disease is lacking. Here, we examined lymphangiogenesis and its potential regulators in perivascular adipose tissue (PVAT) surrounding the heart (C-PVAT) and compared it with PVAT of the internal mammary artery (IMA-PVAT). Forty-six patients undergoing coronary artery bypass graft surgery were included. Periopera ...[more]

PMID: 31324038

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Project description:Background Perivascular adipose tissue (PVAT) is associated with metabolically driven chronic inflammation called metaflammation, which contributes to vascular function and the pathogenesis of vascular disease. The saphenous vein (SV) is commonly used as an essential conduit in coronary artery bypass grafting, but the long-term patency of SV grafts is a crucial issue. The use of the novel "no-touch" technique of SV harvesting together with its surrounding tissue has been reported to result in good long‑term graft patency of SV grafts. Herein, we investigated whether PVAT surrounding the SV (SV-PVAT) has distinct phenotypes compared with other PVATs of vessels. Methods and Results Fat pads were sampled from 48 patients (male/female, 32/16; age, 72±8 years) with coronary artery disease who underwent elective coronary artery bypass grafting. Adipocyte size in SV-PVAT was significantly larger than the sizes in PVATs surrounding the internal thoracic artery, coronary artery, and aorta. SV-PVAT and PVAT surrounding the internal thoracic artery had smaller extents of fibrosis, decreased gene expression levels of fibrosis-related markers, and less metaflammation, as indicated by a significantly smaller extent of cluster of differentiation 11c-positive M1 macrophage infiltration, higher gene expression level of adiponectin, and lower gene expression levels of inflammatory cytokines, than did PVATs surrounding the coronary artery and aorta. Expression patterns of adipocyte developmental and pattern-forming genes were totally different among the PVATs of the vessels. Conclusions The phenotype of SV-PVAT, which may result from inherent differences in adipocytes, is closer to that of PVAT surrounding the internal thoracic artery than that of PVAT surrounding the coronary artery or that of PVAT surrounding the aorta. SV-PVAT has less metaflammation and consecutive adipose tissue remodeling, which may contribute to high long-term patency of grafting when the no-touch technique of SV harvesting is used.

Project description:BackgroundEpicardial adipose tissue (EAT) is closely related to coronary artery disease (CAD). Hemodynamically significant CAD has a worse prognosis and is more likely to benefit from revascularization. However, the specific relationship between EAT and hemodynamically significant CAD remains unclear.MethodsA total of 164 inpatients received single-photon emission computerized tomography-myocardial perfusion imaging (SPECT/MPI) and coronary angiography (CAG) between March 2018 and October 2019 at the Third Affiliated Hospital of Soochow University were enrolled in the retrospective cross-sectional study. Data on body mass index (BMI), hypertension, hyperlipidemia, diabetes mellitus (DM), active smoking, and symptoms were gathered. Epicardial fat volume (EFV) and coronary artery calcium (CAC) were quantified by noncontrast computed tomography (CT). Hemodynamically significant CAD was defined by coronary stenosis severity ≥50% with reversible perfusion defects in the corresponding areas of SPECT/MPI.ResultsA total of 37.8% of patients had hemodynamically significant CAD. Age and BMI increased with tertiles of EFV (P for trend =0.009 and P<0.001). The ratios of hemodynamically significant CAD in EFV from low to high were 16.4%, 37.0%, and 60.0%, respectively (P for the trend <0.001). In univariate regression analysis, EFV was associated with hemodynamically significant CAD [odds ratio (OR) per 10 cm3 =1.36; 95% confidence interval (CI): 1.20-1.55; P<0.001]. After correcting for traditional risk factors and CAC, EFV was firmly linked to hemodynamically significant CAD (OR per 10 cm3 =1.53; 95% CI: 1.25-1.88; P<0.001). With an increasing trend in EFV for the tripartite groups, the likelihood of hemodynamically significant CAD increased significantly (P for trend <0.001). There was a saturation effect between EFV and hemodynamically significant CAD according to the generalized additive model (GAM). When EFV <134.43 cm3, EFV was linearly correlated with hemodynamically significant CAD (OR per 10 cm3 =2.06; 95% CI: 1.45-2.94; P<0.001). When EFV ≥134.43 cm3, the hemodynamically significant CAD risk was steeper and gradually reached saturation. Hypertension affected the relationship between EFV and hemodynamically significant CAD (P for the interaction =0.02) with an interaction effect.ConclusionsThere was a robust relationship between EFV and hemodynamically significant CAD. After adjustment for confounders, we found that the risk of hemodynamically significant CAD onset increased nonlinearly for EFV above 134.4 cm3. This refined understanding of the relationship is helpful for the accurate clinical prediction of hemodynamically significant CAD.

Project description:Background and aimCoronary artery disease (CAD) poses a worldwide health threat. Compelling evidence shows that pericardial adipose tissue (PAT), a brown-like adipose adjacent to the external surface of the pericardium, is associated with CAD. However, the specific molecular mechanisms of PAT in CAD are elusive. This study aims to characterize human PAT and explore its association with CAD.MethodsWe acquired samples of PAT from 31 elective cardiac surgery patients (17 CAD patients and 14 controls). The transcriptome characteristics were assessed in 5 CAD patients and 4 controls via RNA-sequencing. Cluster profile R package, String database, Cytoscape were applied to analyze the potential pathways and PPI-network key to DEGS, whereas the hubgenes were predicted via Metascape, Cytohubba, and MCODE. We use Cibersort, ENCORI, and DGIDB to predict immunoinfiltration, mRNA-miRNA target gene network, and search potential drugs targeting key DEGs. The predictable hubgenes and infiltrating inflammatory cells were validated in 22 patients (12 CAD samples and 10 control samples) through RT-qPCR and immunohistochemistry.ResultsA total of 147 different genes (104 up-regulated genes and 43 down-regulated genes) were identified in CAD patients. These different genes were associated with immunity and inflammatory dysfunction. Cibersort analysis showed monocytes and macrophages were the most common subsets in immune cells, whereas immunohistochemical results revealed there were more macrophages and higher proportion of M1 subtype cells in PAT of CAD patients. The PPI network and module analysis uncovered several crucial genes, defined as candidate genes, including Jun, ATF3, CXCR4, FOSB, CCl4, which were validated through RT-qPCR. The miRNA-mRNA network implicated hsa-miR-185-5p as diagnostic targets and drug-gene network showed colchicine, fenofibrate as potential therapeutic drugs, respectively.ConclusionThis study demonstrates that PAT is mainly associated with the occurrence of CAD following the dysfunction of immune and inflammatory processes. The identified hubgenes, predicted drugs and miRNAs are promising biomarkers and therapeutic targets for CAD.

Dataset Information

Increased Lymphangiogenesis and Lymphangiogenic Growth Factor Expression in Perivascular Adipose Tissue of Patients with Coronary Artery Disease.

Publications

Increased Lymphangiogenesis and Lymphangiogenic Growth Factor Expression in Perivascular Adipose Tissue of Patients with Coronary Artery Disease.

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