TIE1 as a Candidate Gene for Lymphatic Malformations with or without Lymphedema

Michelini, Sandro; Ricci, Maurizio; Vešelényiová, Dominika; Kenanoğlu, Sercan; Kurti, Danjela; Baglivo, Mirko; Fiorentino, A.; Basha, Syed Hussain; Priya, Sasi; Serrani, Roberta; Krajčovič, Juraj; Dündar, Munis; Dautaj, Astrit; Bertelli, Matteo

doi:10.3390/ijms21186780

Cited by 13 publications

(26 citation statements)

References 31 publications

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“…Our study shows that Ang2-Tie signaling co-operates with the VEGF-C-VEGFR3 pathway involved in regulation of the development and growth of lymphatic capillaries and collecting vessels. Notably, our discovery that Ang2 and Tie1 are required for cell surface VEGFR3 expression in the cutaneous lymphatic capillaries is consistent with previous findings that loss-of-function mutations in Ang2, and possibly in Tie1, predispose to lymphedema and hydrops fetalis (29,30,58). In contrast, mutations of Ang1 and Tie2 have been found in glaucoma patients who have increased intraocular pressure and compromised function of the Schlemm's canal (SC), a lymphatic-like vessel that drains the intraocular fluid (59,60).…”

Section: Clinical Implications Of the Crosstalk Between Ang2-tie And ...supporting

confidence: 92%

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Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression

Korhonen¹,

Murtomäki²,

Jha³

et al. 2022

Journal of Clinical Investigation

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Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor-3 (VEGFR3), encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in lymphangiogenesis is not fully understood. Here we used gene deletion, blocking antibodies, transgene induction and gene transfer to study how Ang2, its Tie2 receptor and Tie1 regulate lymphatic vessels. We discovered that VEGF-C-induced Ang2 secretion from lymphatic endothelial cells (LECs) is involved in full Akt activation downstream of phosphoinositide-3 kinase (PI3K). Neonatal deletion of genes encoding the Tie receptors or Ang2 in LECs, or administration of Ang2 blocking antibody decreased VEGFR3 presentation on LECs and inhibited lymphangiogenesis. A similar effect was observed in LECs upon deletion of PI3K catalytic p110α subunit or with small molecule inhibition of a constitutively active PI3K located downstream of Ang2. Deletion of Tie receptors or blockade of Ang2 decreased VEGF-C-induced lymphangiogenesis also in adult mice. Our results reveal important crosstalk between the VEGF-C and Ang signaling pathways and suggest new avenues for therapeutic manipulation of lymphangiogenesis by targeting Ang2-Tie-PI3K signaling.

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Section: Clinical Implications Of the Crosstalk Between Ang2-tie And ...supporting

confidence: 92%

“…Ang2 acts as a Tie2 agonist in lymphatic vessels, as they lack vascular endothelial protein tyrosine phosphatase (VE-PTP/PTPRß), which dephosphorylates Tie2 (27,28). Interestingly, mutations in Ang2 and possible mutations in Tie1 were recently associated with primary lymphedema in humans (29,30).…”

Section: Introductionmentioning

confidence: 99%

Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression

Korhonen¹,

Murtomäki²,

Jha³

et al. 2022

Journal of Clinical Investigation

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“…Genetic testing was performed on genomic DNA extracted from saliva or peripheral blood of probands, as previously described [ 23 ]. Briefly, a custom-made oligonucleotide probe library was designed to capture all coding exons and flanking exon/intron boundaries (±15 bp) of genes known to be associated with lymphedema [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

“…The primary amino acid sequences of NRP1 and NRP2 in FASTA format ( Table 2 ) were used as targets to search template libraries (i.e., the SWISS-MODEL Template Library (version 2019-10-24) and the Protein Data Bank (release 2019-10-18)) [ 26 ] for matching evolution-related structures by means of BLAST [ 27 ] and HHBlits [ 28 ], as previously described [ 23 ]. Briefly, models were based on target-template alignment using ProMod3 of the SWISS-MODEL server [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

Segregation Analysis of Rare NRP1 and NRP2 Variants in Families with Lymphedema

Michelini

Amato

Ricci

et al. 2020

Genes

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Neuropilins are transmembrane coreceptors expressed by endothelial cells and neurons. NRP1 and NRP2 bind a variety of ligands, by which they trigger cell signaling, and are important in the development of lymphatic valves and lymphatic capillaries, respectively. This study focuses on identifying rare variants in the NRP1 and NRP2 genes that could be linked to the development of lymphatic malformations in patients diagnosed with lymphedema. Two hundred and thirty-five Italian lymphedema patients, who tested negative for variants in known lymphedema genes, were screened for variants in NRP1 and NRP2. Two probands carried variants in NRP1 and four in NRP2. The variants of both genes segregated with lymphedema in familial cases. Although further functional and biochemical studies are needed to clarify their involvement with lymphedema and to associate NRP1 and NRP2 with lymphedema, we suggest that it is worthwhile also screening lymphedema patients for these two new candidate genes.

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“…In addition, NFKB2 and FOXC2 have been proposed to be primary factors in lymphangiogenesis and lymphedema since they are involved in both inflammatory reactions and lymph development [ 1 ]. Tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1)—a cell surface protein involved in angiogenesis and lymphangiogenesis—is reportedly related to lymphatic dysfunction, as TIE1 gene variants were identified in 235 lymphedema patients [ 18 ]. The TIE1 receptor-deficient mouse model exhibited abnormal development of lymphatic vessels [ 18 ], indicating that the TIE1 gene may be associated with lymphedema progression.…”

Section: Introductionmentioning

confidence: 99%

Effects of Sodium Selenite Injection on Serum Metabolic Profiles in Women Diagnosed with Breast Cancer-Related Lymphedema—Secondary Analysis of a Randomized Placebo-Controlled Trial Using Global Metabolomics

Lee

Kim

et al. 2021

Nutrients

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In our previous study, intravenous (IV) injection of selenium alleviated breast cancer-related lymphedema (BCRL). This secondary analysis aimed to explore the metabolic effects of selenium on patients with BCRL. Serum samples of the selenium-treated (SE, n = 15) or the placebo-controlled (CTRL, n = 14) groups were analyzed by ultra-high-performance liquid chromatography with Q-Exactive Orbitrap tandem mass spectrometry (UHPLC-Q-Exactive Orbitrap/MS). The SE group showed a lower ratio of extracellular water to segmental water (ECW/SW) in the affected arm to ECW/SW in the unaffected arm (arm ECW/SW ratio) than the CTRL group. Metabolomics analysis showed a valid classification at 2-weeks and 107 differential metabolites were identified. Among them, the levels of corticosterone, LTB4-DMA, and PGE3—which are known anti-inflammatory compounds—were elevated in the SE group. Pathway analysis demonstrated that lipid metabolism (glycerophospholipid metabolism, steroid hormone biosynthesis, or arachidonic acid metabolism), nucleotide metabolism (pyrimidine or purine metabolism), and vitamin metabolism (pantothenate and CoA biosynthesis, vitamin B6 metabolism, ascorbate and aldarate metabolism) were altered in the SE group compared to the CTRL group. In addition, xanthurenic acid levels were negatively associated with whole blood selenium level (WBSe) and positively associated with the arm ECW/SW. In conclusion, selenium IV injection improved the arm ECW/SW ratio and altered the serum metabolic profiles in patients with BCRL, and improved the anti-inflammatory process in lipid, nucleotide and vitamin pathways, which might alleviate the symptoms of BCRL.

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TIE1 as a Candidate Gene for Lymphatic Malformations with or without Lymphedema

Cited by 13 publications

References 31 publications

Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression

Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression

Segregation Analysis of Rare NRP1 and NRP2 Variants in Families with Lymphedema

Effects of Sodium Selenite Injection on Serum Metabolic Profiles in Women Diagnosed with Breast Cancer-Related Lymphedema—Secondary Analysis of a Randomized Placebo-Controlled Trial Using Global Metabolomics

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