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 deactivationdependent, 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.

Changes in TL1A levels and associated cytokines during pathogenesis of diabetic retinopathy

“…Previous studies have reported TL1A to be a negative regulator of proliferation for endothelial cells, resulting in inhibition of vasculogenesis (7,11,12). As DR is a microvascular DM-associated vision disease involving vasculogenesis, the present study investigated the levels of TL1A in the retina of rats with DM by immunohistochemical analysis.…”

“…Additionally, TL1A inhibited ~50% of the neovascularization induced by either FGF2 or VEGF in vivo . A recent study Qi et al (12) determined that TL1A inhibited vasculogenesis by regulating the expression levels of the VEGFR1. They also reported that TL1A inhibited VEGF-driven, EPC-supported vasculogenesis in a murine matrigel implant model (12).…”

“…TL1A may inhibit the proliferation of endothelial cells by two mechanisms, the induction of early G 1 phase arrest and programmed cell death in proliferating cells (11). In addition, TL1A has been reported to inhibit vasculogenesis by regulation of soluble isoforms of VEGF receptor 1 (VEGFR1) (12). DR is a microvascular DM-associated vision disease with severe negative effects on the quality of life of patients.…”

IL12Rβ1ΔTM Is a Secreted Product ofil12rb1That Promotes Control of Extrapulmonary Tuberculosis

“…The IL6R␣ splice variant enhances IL-6's activities in the mouse central nervous system, leading to changes in body temperature and locomotor activity (51), while IL6R␣/IL-6 double transgenic mice display increases in hepatic hematopoiesis and hepatocellular hyperplasia (52,53). Spliced IL7R␣ exacerbates experimental autoimmune encephalomyelitis (47), while signal-mediated changes in VEGFR1 splicing alters vasculogenesis in tissue culture models systems (54). Increased serum concentrations of select cytokine receptor splice variants can also be indicative of an underlying pathology.…”

Increased cardiac remodeling in cardiac-specific Flt-1 receptor knockout mice with pressure overload

“…Vascular endothelial growth factor (VEGF) is a wellknown signal protein that stimulates vasculogenesis and angiogenesis and is a soluble dimeric glycoprotein that serves as a strong endothelial cell-specific mitogen of blood vessels (Choi et al 2014;Qi et al 2013). VEGF mediates various angiogenic cellular responses such as survival, migration, and differentiation via the activation of a series of signaling within endothelial cells and is secreted from cardiomyocytes in response to extracellular stimuli (Tirziu et al 2007;Tsoporis et al 2012).…”