Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15

Abstract

Hemangioblastoma (HB) is an abnormal intracranial buildup of blood vessels that exhibit a great potential for hemorrhage. Surgical options are limited, and few medications are available for treatment. We show here by immunohistochemical analysis that HB lesions display highly increased levels of VEGF expression and macrophage/microglia infiltration compared with those in normal brain tissues. In the meantime, TNF superfamily 15 (TNFSF15) (also known as vascular endothelial growth inhibitor), an antiangiogenic cytokine, is highly expressed in normal brain blood vessels but diminished in HB lesions. We set up a brain hemangioma model by using mouse bEnd.3 cells of a T antigen—transformed endothelial cell line that produce a large amount of VEGF. When implanted in mouse brains, these cells form lesions that closely resemble the pathologic characteristics of HB. Retroviral infection of bEnd.3 cells with TNFSF15 leads to inhibition of VEGF production and retardation of hemangioma formation. Similar results are obtained when wild‐type bEnd.3 cells are implanted in the brains of transgenic mice overexpressing TNFSF15. Additionally, TNFSF15 treatment results in enhanced pericyte coverage of the blood vessels in the lesions together with reduced inflammatory cell infiltration and decreased hemorrhage. These findings indicate that the ability of TNFSF15 to counterbalance the abnormally highly angiogenic and inflammatory potential of the microenvironment of HB is of therapeutic value for the treatment of this disease.—Yang, G.‐L., Han, Z., Xiong, J., Wang, S., Wei, H., Qin, T.‐T., Xiao, H., Liu, Y., Xu, L.‐X., Qi, J.‐W., Zhang, Z.‐S., Jiang, R., Zhang, J., Li, L.‐Y. Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15. FASEB J. 33, 10505–10514 (2019). http://www.fasebj.org

A Protective Role of Tumor Necrosis Factor Superfamily-15 in Intracerebral Hemorrhage-Induced Secondary Brain Injury

“…To determine the impact of TNFSF15 on early brain injury in ICH, we set-up an ICH model by intracranial injection of collagenase into the ipsilateral hemispheres of TNFSF15-overexpressing transgenic mice (SPC-TNFSF15) ( Yang et al, 2019 ) and their transgene-negative littermates. We measured the ICH lesion volume with Luxol fast blue/cresyl violet staining on day 3 postinjury, and found that the lesion volumes in the TNFSF15 group were about 50% of those in the littermates ( Figure 1A and B ).…”

“…It is plausible that TNFSF15 actions contribute to the reduction of the extent of inflammation in the acute phase of ICH. Decreased leukocyte recruitment after TNFSF15 treatment has been observed in three different brain disease models, including collagenase-induced ICH, intracranial hemangioma ( Yang et al, 2019 ), and TBI ( Gao et al, 2015 ). VEGF is known to induce macrophage/microglia activation and migration to an inflammation site via VEGFR1 on macrophage/microglia ( Kerber et al, 2008 ) and to recruit MMP-9 expressing neutrophils ( Christoffersson et al, 2012 ).…”

“…The SPC-TNFSF15-transgenic mouse strain (C57BL/6 background) was established in the laboratory of L.-Y.L (Qin et al, 2015;Yang et al, 2017Yang et al, , 2019. In this study, 8-week-old female SPC-TNFSF15-transgenic mice and the transgene-negative littermates were used.…”

“…Tumor necrosis factor superfamily-15 (TNFSF15), also known as vascular endothelial growth inhibitor (VEGI or TL1A), is a cytokine produced predominantly by endothelial cells in the blood vessels of brain and other normal tissues ( Chew et al, 2002 ; Yang et al, 2019 ; Zhai et al, 1999 ). TNFSF15 has been shown to inhibit endothelial cell proliferation by enforcing a growth arrest on quiescent endothelial cells while inducing apoptosis in proliferating endothelial cells ( Yu et al, 2001 ).…”

“…TNFSF15 has been shown to inhibit endothelial cell proliferation by enforcing a growth arrest on quiescent endothelial cells while inducing apoptosis in proliferating endothelial cells ( Yu et al, 2001 ). It has been shown in a mouse model of intracranial hemangioma that TNFSF15 treatment has an inhibitory effect on intracranial hemangioma growth, lesion-associated hemorrhage, activation of macrophage/microglia, and the infiltration of MMP-9 + neutrophils into intracranial hemangioma, giving rise to elevated vascular stability ( Yang et al., 2019 ). Similarly, TNFSF15 treatment has been shown in a mouse model of traumatic brain injury (TBI) to reduce the contusion brain tissue loss, the permeation of inflammatory cells, and the activation of microglia, as well as up-regulation of tight junction proteins in endothelial cells, with an overall effect of reduced vascular permeability in the ipsilateral hemisphere ( Gao et al, 2015 ).…”