Biomechanical forces generated by fluid flow regulate endothelial cell biology in vascular transport systems. Several lines of evidence indicate that disturbed flow in blood vessels corresponds with vascular disease and dysregulated endothelial cell turnover; however, flow-dependent effects on endothelial cells in the lymphatic vasculature have not been well defined. Amélie Sabine and colleagues of the University of Lausanne determined that the transcription factor FOXC2 maintains normal lymphatic endothelial cell morphology and vascular integrity during disturbed flow. FOXC2 was highly expressed in cultured lymphatic endothelial cells (LECs) exposed to disturbed flow, in contrast to cells exposed to static conditions. Under conditions of oscillatory disturbed flow, FOXC2-deficient LECs exhibited an abnormal shear stress response, resulting in aberrant intercellular junctions caused by increased contraction of actin stress fibers. Loss of FOXC2 also induced excessive LEC proliferation due to loss of FOXC2-mediated suppression of the transcriptional co-activator TAZ. In murine models, induction of LEC-specific Foxc2 deletion resulted in loss of vessel integrity and consequent lymph leakage, lymphatic valve degeneration, and mortality. Together, these results provide important insight into how lymph flow regulates LEC biology. Moreover, as FOXC2 mutations underlie lymphedema-distichiasis, a human disease of the lymphatic vasculature, this study provides a mouse model that may facilitate further studies into the pathogenesis of this disease. The accompanying false-colored electron micrographs show LEC junctions in the thoracic duct of WT (left) mice and mice with induced deletion of Foxc2 in LECs (right). Note the disruption of the endothelium and the formation of a large vacuolar structure in the mutant animals. Moreover, the “interdigitating” contacts between neighboring cells (pseudo-colored pink and blue) observed in the WT animals are lost in the mutant animals.
Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells,
Amélie Sabine, Esther Bovay, Cansaran Saygili Demir, Wataru Kimura, Muriel Jaquet, Yan Agalarov, Nadine Zangger, Joshua P. Scallan, Werner Graber, Elgin Gulpinar, Brenda R. Kwak, Taija Mäkinen, Inés Martinez-Corral, Sagrario Ortega, Mauro Delorenzi, Friedemann Kiefer, Michael J. Davis, Valentin Djonov, Naoyuki Miura, Tatiana V. Petrova