title: TNFSF15 inhibits vasculogenesis by regulating relative levels of membrane-bound and soluble isoforms of VEGF receptor 1.
abstract: Mouse bone marrow-derived Lin(-)-Sca-1(+) endothelial progenitor cell (EPC) has pluripotent abilities such as supporting neovascularization. Vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) (Flt1) recognizes various VEGF isoforms and is critically implicated in a wide range of physiological and pathological settings, including vasculogenesis. Mouse EPC expresses two isoforms of VEGFR1: mFlt1, which transmits ligand-induced signals; and sFlt1, which acts as a negative regulator by sequestering ligands of VEGF receptors. How the relative levels of mFlt1 and sFlt1 are regulated is not yet clear. We report here that tumor necrosis factor superfamily 15 (TNFSF15) (also known as VEGI or TL1A), an endothelial cell-secreted cytokine, simultaneously promotes mFlt1 degradation and up-regulates sFlt1 expression in EPC, giving rise to disruption of VEGF- or PlGF-induced activation of eNOS and MAPK p38 and effective inhibition of VEGF-driven, EPC-supported vasculogenesis in a murine Matrigel implant model. TNFSF15 treatment of EPC cultures facilitates Akt deactivation-dependent, ubiquitin-assisted degradation of mFlt1 and stimulates sFlt1 expression by activating the PKC, Src, and Erk1/2 signaling pathway. Additionally, TNFSF15 promotes alternative splicing of the Flt1 gene in favor of sFlt1 production by down-regulating nuclear protein Jumonji domain-containing protein 6 (Jmjd6), thus alleviating Jmjd6-inhibited sFlt1 expression. These findings indicate that TNFSF15 is a key component of a molecular mechanism that negatively modulates EPC-supported vasculogenesis through regulation of the relative levels of mFlt1 and sFlt1 in EPC.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and Nankai University College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Tianjin 300071, China.
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Qi
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Qin
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Xu
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.forename: Gui-Li
authors.initials: GL
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Huai-Yuan
authors.initials: HY
authors.lastname: Xiao
authors.forename: Zhi-Song
authors.initials: ZS
authors.lastname: Zhang
authors.forename: Lu-Yuan
authors.initials: LY
authors.lastname: Li
mesh_terms: D017398:Alternative Splicing / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D007797:Laminin; D008024:Ligands; D051379:Mice; D008856:Microscopy, Fluorescence; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism; D011509:Proteoglycans; D059748:Proteolysis; D013234:Stem Cells / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000378:metabolism / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D004338:Drug Combinations; D007797:Laminin; D008024:Ligands; D020033:Protein Isoforms; D011509:Proteoglycans; C505947:Tnfsf15 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; C059485:matrigel; D003094:Collagen; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: angiogenesis; protein degradation
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