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PMID:18726995

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Citation

Rege, TA, Stewart, J Jr, Dranka, B, Benveniste, EN, Silverstein, RL and Gladson, CL (2009) Thrombospondin-1-induced apoptosis of brain microvascular endothelial cells can be mediated by TNF-R1. J. Cell. Physiol. 218:94-103

Abstract

Thrombospondin-1 (TSP-1) treatment of dermal microvascular endothelial cells (MvEC) has been shown to upregulate Fas ligand (FasL) and to induce apoptosis by a mechanism that requires caspase-8 activity. We have examined the potential anti-angiogenic effects of TSP-1 on primary human brain MvEC. The addition of TSP-1 to primary human brain MvEC cultured as monolayers on type 1 collagen, induced cell death and apoptosis (evidenced by caspase-3 cleavage) in a dose- (5-30 nM) and time-dependent (maximal at 17 h) manner. TSP-1 treatment for 17 h induced caspase-3 cleavage that required caspase-8 activity and the tumor necrosis factor receptor 1 (TNF-R1). We did not find a requirement for Fas, or the tumor necrosis-related apoptosis-inducing ligand receptors (TRAIL-R) 1 and 2. We confirmed the findings using caspase inhibitors, blocking antibodies and small interfering RNA (siRNA). Further analysis indicated that the TSP-1 induction of caspase-3 cleavage of primary human brain MvEC adherent to collagen required the synthesis of new message and protein, and that TSP-1 induced the expression of TNFalpha mRNA and protein. Consistent with these findings, when the primary human brain MvEC were propagated on collagen gels mAb anti-TNF-R1 reversed the inhibitory effect, in part, of TSP-1 on tube formation and branching. These data identify a novel mechanism whereby TSP-1 can inhibit angiogenesis-through induction of apoptosis in a process mediated by TNF-R1.

Links

PubMed PMC2597846 Online version:10.1002/jcp.21570

Keywords

Antigens, CD36/metabolism; Apoptosis/drug effects; Base Sequence; Brain/cytology; Brain/metabolism; Caspase 3/metabolism; Cells, Cultured; Endothelial Cells/cytology; Endothelial Cells/drug effects; Endothelial Cells/metabolism; Humans; Microcirculation/drug effects; Neovascularization, Physiologic/drug effects; RNA, Messenger/genetics; RNA, Messenger/metabolism; RNA, Small Interfering/genetics; Receptors, Tumor Necrosis Factor, Type I/antagonists & inhibitors; Receptors, Tumor Necrosis Factor, Type I/genetics; Receptors, Tumor Necrosis Factor, Type I/metabolism; Thrombospondin 1/pharmacology; Tumor Necrosis Factor-alpha/genetics; Tumor Necrosis Factor-alpha/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TSP1

involved_in

GO:0032760: positive regulation of tumor necrosis factor production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSP1

involved_in

GO:2000353: positive regulation of endothelial cell apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSP1

involved_in

GO:1902043: positive regulation of extrinsic apoptotic signaling pathway via death domain receptors

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSP1

involved_in

GO:0016525: negative regulation of angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSP1

involved_in

GO:0042535: positive regulation of tumor necrosis factor biosynthetic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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