Abstract
Mutations in the transcription factor FOXC2 are predominately associated with lymphedema. Herein, we demonstrate a key role for related factor FOXC1, in addition to FOXC2, in regulating cytoskeletal activity in lymphatic valves. FOXC1 is induced by laminar, but not oscillatory, shear and inducible, endothelial-specific deletion impaired postnatal lymphatic valve maturation in mice. However, deletion of Foxc2 induced valve degeneration, which is exacerbated in Foxc1; Foxc2 mutants. FOXC1 knockdown (KD) in human lymphatic endothelial cells increased focal adhesions and actin stress fibers whereas FOXC2-KD increased focal adherens and disrupted cell junctions, mediated by increased ROCK activation. ROCK inhibition rescued cytoskeletal or junctional integrity changes induced by inactivation of FOXC1 and FOXC2 invitro and vivo respectively, but only ameliorated valve degeneration in Foxc2 mutants. These results identify both FOXC1 and FOXC2 as mediators of mechanotransduction in the postnatal lymphatic vasculature and posit cytoskeletal signaling as a therapeutic target in lymphatic pathologies.
Highlights
The lymphatic vasculature has a critical role in maintaining tissue homeostasis by returning interstitial fluid to the venous circulation, absorbing lipids from the digestive tract, and providing a network for immune surveillance and response (Adams and Alitalo, 2007; Zheng et al, 2014; Norden and Kume, 2020)
Previous work from our group has demonstrated the critical role for FOXC2 in postnatal lymphatic vascular function (Sabine et al, 2015) and we have shown that endothelial cell (EC)-specific deletion of Foxc1 during murine embryonic development impairs lymphatic valve maturation (Fatima et al, 2016)
Mutations associated with the VEGF-C/VEGR3 signaling pathway, including changes in FOXC2, as well as key transcription factors involved in lymphatic endothelial cells (LECs) specification, such as Sox-18 and GATA2, contribute to the development of primary lymphedema (Aspelund et al, 2016; Jiang et al, 2018)
Summary
The lymphatic vasculature has a critical role in maintaining tissue homeostasis by returning interstitial fluid to the venous circulation, absorbing lipids from the digestive tract, and providing a network for immune surveillance and response (Adams and Alitalo, 2007; Zheng et al, 2014; Norden and Kume, 2020). During murine embryonic development at E15.5, the primitive lymphatic vascular plexus remodels and is reorganized into capillaries, pre-collectors and collecting vessels characterized by differential protein expression patterns, cell-cell junctions, and mural cell recruitment (Schulte-Merker et al, 2011). Coinciding with the remodeling of this plexus is the formation of intraluminal, bi-leaflet valves in the collecting vessels that function to prevent lymph backflow (Bazigou and Makinen, 2013). Critical to lymphatic valve formation, FOXC2 and GATA2 are upregulated in lymphatic endothelial cells (LECs) in response to oscillatory shear stress (OSS) forces (Kazenwadel et al, 2015; Sabine et al, 2012). In valve forming cells that express high levels of the master lymphatic regulator PROX1, FOXC2 cooperates with PROX1 to control intraluminal
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