Lymphatic-specific intracellular modulation of receptor tyrosine kinase signaling improves lymphatic growth and function.

Autor:	Kataru RP; Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. katarur@mskcc.org., Baik JE; Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Park HJ; Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Ly CL; Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Shin J; Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Schwartz N; Autoimmunity and Inflammation Program and Rheumatology, Hospital for Special Surgery, New York, NY 10021, USA., Lu TT; Autoimmunity and Inflammation Program and Rheumatology, Hospital for Special Surgery, New York, NY 10021, USA.; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10021, USA., Ortega S; Transgenic Mice Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, 20829, Spain., Mehrara BJ; Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2021 Aug 10; Vol. 14 (695). Date of Electronic Publication: 2021 Aug 10.
DOI:	10.1126/scisignal.abc0836
Abstrakt:	Exogenous administration of lymphangiogenic growth factors is widely used to study changes in lymphatic function in pathophysiology. However, this approach can result in off-target effects, thereby generating conflicting data. To circumvent this issue, we modulated intracellular VEGF-C signaling by conditionally knocking out the lipid phosphatase PTEN using the Vegfr3 promoter to drive the expression of Cre-lox in lymphatic endothelial cells (LECs). PTEN is an intracellular brake that inhibits the downstream effects of the activation of VEGFR3 by VEGF-C. Activation of Cre-lox recombination in adult mice resulted in an expanded functional lymphatic network due to LEC proliferation that was independent of lymphangiogenic growth factor production. Furthermore, compared with lymphangiogenesis induced by VEGF-C injection, LEC PTEN animals had mature, nonleaky lymphatics with intact cell-cell junctions and reduced local tissue inflammation. Last, compared with wild-type or VEGF-C-injected mice, LEC PTEN animals had an improved capacity to resolve inflammatory responses. Our findings indicate that intracellular modulation of lymphangiogenesis is effective in inducing functional lymphatic networks and has no off-target inflammatory effects. (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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