biostudies-literatureKataru RPEmerson Collective Cancer Research FundNIAID NIH HHSNHLBI NIH HHSNCI NIH HHSNational Institutes of HealthNIAMS NIH HHSeabc0836https://www.ebi.ac.uk/biostudies/studies/S-EPMC8567054biostudies-literatureUnknown14(695)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 <i>Vegfr3</i> promoter to drive the expression of <i>Cre-lox</i> 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 lympScience signalingLymphatic-specific intracellular modulation of receptor tyrosine kinase signaling improves lymphatic growth and function.PMC8567054T32 CA009501HL111130R01 HL111130P30 CA008748R01 AI079178T32 AR071302691032Baik JELu TTOrtega SPark HJShin JLy CLMehrara BJKataru RPSchwartz NfalseLymphatic-specific intracellular modulation of receptor tyrosine kinase signaling improves lymphatic growth and function.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 <i>Vegfr3</i> promoter to drive the expression of <i>Cre-lox</i> 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 lymp2021-01-01T00:00:00Z2021 Aug2025-04-22T22:04:07.405Z2025-04-06T03:54:03.714ZS-EPMC85670543437657010.1126/scisignal.abc0836