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- Title
Lymphatic-specific intracellular modulation of receptor tyrosine kinase signaling improves lymphatic growth and function.
- Authors
Kataru, Raghu P.; Baik, Jung Eun; Park, Hyeung Ju; Ly, Catherine L.; Shin, Jinyeon; Schwartz, Noa; Lu, Theresa T.; Ortega, Sagrario; Mehrara, Babak J.
- Abstract
Less leaky lymphatics: The lymphatic system enables drainage of excess fluid from tissues and immune cell migration during inflammatory responses. Attempts to increase lymphatic vessel density have generally relied on the exogenous administration of the lymphangiogenic growth factor VEGF-C, which yields leaky and less functional lymphatics and off-target inflammation. Kataru et al. generated mice with a lymphatic endothelial cell–specific deficiency of the lipid phosphatase PTEN, reasoning that the absence of PTEN would promote signaling downstream of VEGFR3, a key receptor for VEGF-C (see also the Focus by Künnapuu and Jeltsch). These mice had an expanded lymphatic vessel network that was not leaky and that contributed to improved resolution of inflammation, compared to control mice injected with VEGF-C. These results suggest that a better approach to increasing lymphangiogenesis may be to enhance signaling downstream of VEGFR3. 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, LECPTEN 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, LECPTEN 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.
- Subjects
GROWTH factors; PATHOLOGICAL physiology; LYMPHATICS; INFLAMMATION; FACTORS of production; PROTEIN-tyrosine kinases
- Publication
Science Signaling, 2021, Vol 14, Issue 695, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abc0836