FGF2-induced Ras/Erk MAPK signalling maintains lymphatic endothelial cell identity by up-regulating endothelial cell-specific gene expression and suppressing TGFβ signalling via Smad2

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<jats:p>The lymphatic endothelial cell (LEC) fate decision program during development has been revealed. However, the mechanism underlying the maintenance of differentiated LEC identity remains largely unknown. Here, we show that fibroblast growth factor 2 (FGF2) plays a fundamental role in maintaining a differentiated LEC trait. In addition to demonstrating the appearance of alpha-smooth muscle actin (αSMA) expressing LECs in mouse lymphedematous skin in vivo, we found that mouse-immortalized LECs lose their characteristics and undergo endothelial-to-mesenchymal transition (EndMT) when cultured in FGF2-depleted medium. FGF2 depletion acted synergistically with transforming growth factor (TGF) β to induce EndMT. We also found that H-Ras-overexpressing LECs were resistant to EndMT. Ras activation not only upregulated FGF2-induced Erk MAPK activation, but also suppressed TGFβ-induced activation of Smad2 by modulating Smad2 phosphorylation via Erk MAPKs. These results suggest that FGF2 may regulate LEC-specific gene expression and suppress TGFβ signalling in LECs via Smad2 in a Ras/Erk MAP kinase-dependent manner. Taken together, our findings provide a new insight into the FGF2/Ras/Erk MAPK-dependent mechanism that maintains and modulates the LEC trait.</jats:p>

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