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• Review Volume 11, Issue 16 pp 6602-6613

  Pathophysiology of aged lymphatic vessels

  Relevance score: 15.504693

  Tongyao Shang, Jiangjiu Liang, Carolyn M. Kapron, Ju Liu

  Keywords: aging, lymphatic vessels, endothelial cells

  Published in Aging on August 28, 2019

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  Lymphatic vessels maintain body homeostasis by recirculation of fluid and cells. Cell senescence induces lymphatic dysfunction. Impaired contractile function is caused by low muscle cell investiture and decrease of nitric oxide in aged lymphatic collectors, leading to poor drainage of lymph. Aging-induced loss of endothelial glycocalyx and production of inflammatory cytokines increases permeability of lymphatic vessels. In addition, aging-associated basal activation of mast cells delays immune response. In this review, we summarize the structural and pathological changes of aged lymphatic vessels, and discuss the underlying molecular mechanisms.

  

  Lymph transport along lymphatic vessels. (A) Unidirectional lymph flow route: lymphatic capillaries collect peripheral tissue fluid and converge into larger collecting vessels, then lymph drains into the lymph node from the afferent lymphatic vessels and flows out from the efferent lymphatic vessel. Afterwards lymph fluid flows through the thoracic duct and the right lymphatic trunk, eventually enters into venous circulation. Arrows indicate the direction of lymph flow. (B) Interstitial fluid, macromolecules and immune cells which extravasate from blood vessels are collected by lymphatic capillaries. Initial lymphatics are composed of a layer of oak leaf-shaped endothelial cells and lack of muscle layers. (C) Lymphatic collectors contain intraluminal valve and SMC layers that enable the unidirectional lymph flow.

  
  
  

  

  NO–dependent regulatory mechanisms in aged lymphatic vessels. (A) In adult lymphatic vessels, the enhanced eNOS activity mediates the transient inhibition of contraction frequency to adapt the load by the increase of imposed flow. (B) In aged lymphatic vessels, increased iNOS level renders the contractile parameters unchanged in response to increased imposed flow.

  
  
  

  

  Glycocalyx layer and intercellular junctions of lymphatic vessels during the aging process. (A) In adult lymphatic vessels, the intact, continuous glycocalyx layer covers lymphatic endothelial cells. Detailed view in the box shows the normal glycocalyx layer and intercellular junctions. (B) Aged lymphatic vessels display thin, discontinuous glycocalyx layer. Detailed view in the box shows a significant loss of glycocalyx and adherens/tight junctions. Increased pro-apoptotic factor bak activates caspase-3 to disrupt the downstream protein β-catenin, which leads to decreased adherens junctions and impaired barrier function.

  
  
  

  

  Mast cells in peri-lymphatic tissues. (A) Lower level pre-activation of mast cells in adult peri-lymphatic tissues under resting conditions. (B) In aged peri-lymphatic tissues, increased number of mast cells are activated and secret massive amounts of histamine, leading to hyperpermeability of lymphatic vessels.

  
  
  

• Research Paper Volume 11, Issue 16 pp 6503-6521

  Procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 are potential prognostic indicators in patients with clear cell renal cell carcinoma

  Relevance score: 15.504693

  Wen-Hao Xu, Yue Xu, Jun Wang, Xi Tian, Junlong Wu, Fang-Ning Wan, Hong-Kai Wang, Yuan-Yuan Qu, Hai-Liang Zhang, Ding-Wei Ye

  Keywords: aging, lymphatic vessels, endothelial cells

  Published in Aging on August 25, 2019

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  Intratumoral fibrosis is a frequent histologic finding in highly vascularized clear cell renal cell carcinoma (ccRCC). Here, we investigated the expression of a family of collagen-modifying enzymes, procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 (PLOD1/2/3), in ccRCC tissues and assessed the prognostic value of wild-type and genetically mutated PLOD1/2/3 for ccRCC patients. Normal kidney and ccRCC mRNA and protein expression datasets were obtained from Oncomine, The Cancer Genome Atlas, and Human Protein Atlas databases. Associations between PLOD1/2/3 expression, clinicopathological variables, and patient survival were evaluated using Cox regression and Kaplan–Meier analyses. PLOD1/2/3 mRNA and protein expression levels were significantly elevated in ccRCC tissues compared with normal kidney. Increased PLOD1/2/3 mRNA expression was significantly associated with advanced tumor stage, high pathological grade, and shorter progression-free and overall survival (all p<0.01). Genetic mutation of PLOD1/2/3 was present in ~3% of ccRCC patients and was associated with significantly poorer prognosis compared with expression of wild-type PLOD1/2/3 (p<0.001). This study thus identifies tumor expression of wild-type or mutated PLOD1/2/3 mRNA as a potential predictive biomarker for ccRCC patients and sheds light on the underlying molecular pathogenesis of ccRCC.

  

  Transcriptional expression of PLODs in 20 different types of cancer diseases from Oncomine database. Difference of transcriptional expression was compared by Students’ t-test. Cut-off of p value and fold change were as following: p value=0.01, Fold Change=1.5, gene rank=10%, data type: mRNA.

  
  
  

  

  Transcriptional expression of distinct PLODs family members in ccRCC tumor tissues and adjacent normal renal tissues. (A–C) Differential mRNA expressions of 3 PLODs family members were demonstrated to be highly expressed in primary tumor tissues compared to normal samples (*** p<0.001).

  
  
  

  

  Representative proteins expressions of IHC images of distinct PLODs family members were detected in ccRCC and normal tissues (Human Protein Atlas). (A–C) PLOD1/3 proteins were found not expressed in normal renal tissues, while significantly high staining expressions were observed in ccRCC tissues. (B) PLOD2 protein was detected low expressed in normal renal tissues, while high protein expressions were observed in ccRCC tissues.

  
  
  

  

  Relationship between transcriptional expressions of distinct PLODs family members and individual cancer stages and pathological grade of ccRCC patients. (A–C) Transcriptional expressions of PLOD1, PLOD2 and PLOD3 were significantly correlated with individual cancer stages, patients who were in more advanced stages tended to express higher mRNA expression of PLODs. (D–F) Transcriptional expressions of PLOD1, PLOD2 and PLOD3 were significantly correlated with individual pathological grade, patients who were in more advanced grade score tended to express elevated mRNA expression of PLODs. The highest mRNA expressions of PLODs were found in stage 4 or grade 4. *p<0.05, **p<0.01, ***p<0.001. (G) Hierarchical partitioning was performed using transcriptional expression profiles of PLODs in a heat map. Color gradients suggest high (red) or low (blue) expression level, indicating a trend that higher AJCC stage was associated with elevated PLODs expression.

  
  
  

  

  Kaplan-Meier survival analyses on differential PLOD1/2/3 expression groups with PFS. (A–C) and OS (D–F) in the included 533 ccRCC patients. Compared with low mRNA expression of PLODs, high PLOD1 expressions were significantly correlated with poor PFS (p=0.002) and OS (p<0.001), high PLOD2 expressions were significantly associated with poor PFS (p=0.001) and OS (p<0.001), and elevated PLOD3 expressions were significantly correlated with shorter PFS (p=0.018) and OS (p<0.001).

  
  
  

  

  Genetic mutations in PLODs family members and their association with OS and DFS of ccRCC patients (cBioPortal). A total of 3.1% mutation rate of PLODs was observed in ccRCC patients. Genetic mutation alterations rate of PLOD1, PLOD2 and PLOD3 were 0.4%, 1.2% and 1.5%, respectively (A). Genetic alterations in PLODs were associated with shorter OS (B) and DFS (C) of ccRCC patients.

  
  
  

  

  Functions enrichment and signaling pathways analysis of the mutations in PLODs and their 45 frequently altered neighbor genes in ccRCC patients. (A) Network of PLODs and their 45 frequently altered neighbor genes was constructed using cBioPortal. (B) The functional annotation analysis of PLOD1/2/3 was constructed using ClueGO, a plug-in of Cytoscape. Corrected p-value <0.01 was considered statistically significant. (C) Functional and pathway enrichment analyses of PLOD1/2/3 were performed using DAVID and visualized in bubble chart. (D) Functional and pathway enrichment analyses of 48 involved genes were performed using DAVID and visualized in bubble chart.

  
  
  

  

  GSEA was used to perform hallmark signaling analysis in PLOD1/2/3, respectively. A total of 100 significant genes were obtained from GSEA with positive and negative correlation. The most involved significant pathways included glycolysis, hypoxia, epithelial mesenchymal transition, etc.