Modulation of Vascular and Lymphatic Endothelial Functions by TNFSF15

Vasculogenesis and lymphangiogenesis are important aspects of cancer development, progression, and metastasis. We have found that tumor necrosis factor superfamily-15 (TNFSF15, also known as VEGI or TL1A), a cytokine predominantly produced by endothelial cells, is able to modulate the activities of VEGF receptor-1, -2, and -3. TNFSF15 negatively modulates endothelial progenitor cell-supported vasculogenesis by simultaneously promoting degradation of membrane-bound form of VEGFR1 (mFlt1) that mediates VEGF-stimulated vasculogenesis, while upregulating the expression of soluble form of VEGFR1 (sFlt1) that scavenges VEGF and thus inhibits its activities. In addition, TNFSF15 is part of a molecular mechanism that prevents VEGF-induced vascular hyperpermeability by inhibiting VEGF-induced VEGFR2-phosphorylation, resulting in diminished VEGFR2-mediated signals and reduced endothelial permeability. Examined in animal models, the ability of topically applied VEGF to induce vessel leakage is markedly lowered in the skin of TNFSF15-overexpressing transgenic mice compared with that in the transgene-negative littermates. Similar results are obtained when wild-type mice are treated with recombinant TNFSF15 by intraperitoneal injection. Moreover, TNFSF15 can promote lymphatic endothelial cell (LEC) growth and migration, stimulate lymphangiogenesis, and facilitate lymphatic function. Treatment of mouse LEC with TNFSF15 results in upregulation of VEGFR3 expression. TNFSF15-overexpressing transgenic mice exhibit a marked enhancement of lymph drainage. Death domain-containing receptor-3 (DR3), a cell-surface receptor of the TNF receptor superfamily (TNFRSF25), mediates the abovementioned TNFSF15 activities. These findings are consistent with the view that, via intervention with the signaling pathways of VEGF and its receptors VEGFR1, VEGFR2, and VEGFR3, TNFSF15 plays a key role in the modulation of the functions of both vascular and lymphatic endothelia.