TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype

Abstract

Pathological angiogenesis associated with wound healing often occurs subsequent to an inflammatory response that includes the secretion of cytokines such as tumor necrosis factor (TNF). Controversy exists on the angiogenic actions of TNF, with it being generally proangiogenic in vivo, but antiangiogenic in vitro. We find that whereas continuous administration of TNF in vitro or in vivo inhibits angiogenic sprouting, a 2-to 3-day pulse stimulates angiogenesis by inducing an endothelial "tip cell" phenotype. TNF induces the known tip cell genes plateletderived growth factor B (PDGFB) and vascular endothelial cell growth factor receptor-2 (VEGFR2), while at the same time blocking signaling through VEGFR2, thus delaying the VEGF-driven angiogenic response. Notch signaling regulates tip cell function, and we find that TNF also induces the notch ligand jagged-1, through an NFB-dependent mechanism. Enrichment of jagged-1 in tip cells was confirmed by immunofluorescent staining as well as by laser capture microdissection/quantitative reversetranscription-polymerase chain reaction IntroductionNeovascularization, or the formation of new blood vessels, is a critical component of many physiologic as well as pathologic conditions, including development, reproduction, wound healing, diabetic retinopathy, and tumor growth. During wound healing, new vessel growth by angiogenesis is a necessary early step in rebuilding tissue, however the coordination of angiogenesis with the resolution of the acute inflammatory stage is not well understood. The earliest events after tissue damage include the generation of a fibrin clot and the bursting of platelets to release numerous growth factors. Fibrin provides a provisional matrix that promotes the accumulation of blood-derived monocytes that then differentiate into tissue macrophages. Activated macrophages synthesize several cytokines, including tumor necrosis factor (TNF), which activate local endothelial cells (ECs) and promote leukocyte recruitment. After 3 to 4 days, when the initial infection has been cleared, there is a switch toward tissue repair and concomitant with this is the acceleration of angiogenesis. 1,2 TNF is a major inflammatory mediator that induces multiple changes in EC gene expression including induction of adhesion molecules, integrins, and matrix metalloproteinases (MMPs). Its effects on angiogenesis have been the subject of some controversy. For example, TNF blocks EC proliferation and migration in vitro [3][4][5] and has been reported to down-regulate activity 6 and expression 7,8 of vascular endothelial cell growth factor receptor-2 (VEGFR2). On the other hand, TNF has also been shown to up-regulate VEGFR2 expression 9 and promote EC migration. 10 In vivo the situation is no clearer: TNF promotes angiogenesis in the cornea, 3,11 whereas loss of TNFR1 (p55 receptor) leads to enhanced angiogenesis in both retina 12 and wounded skin. 13 Further studies with TNF receptor-deficient mice have demonstrated enhanced hind limb angiogenesis after temporary ischemia in T...

TNF-α alters the inflammatory secretion profile of human first trimester placenta

“…43 This speculation is based, eg, on angiogenesis studies showing predominantly anti-angiogeneic effects of TNF-α on in vitro-cultured endothelial cells, but pro-angiogeneic activities in vivo. 44 Maternal TNF-α plasma levels range within the concentration of pg/ml in healthy, pregnant women and are increased in GDM and preeclamptic women. [45][46][47] In the present study, TNF-α at concentrations of 1 and 10 ng/ml were used, which are in fact higher than observed in vivo levels.…”

Placental Mesenchymal Stromal Cells Derived from Blood Vessels or Avascular Tissues: What Is the Better Choice to Support Endothelial Cell Function?

“…In addition, it needs to be taken into account that angiogenesis is a complex process, and that it remains a challenge to determine the interaction of the factors involved. Controversy exists, among others, on the angiogenic actions of certain proteins, including TNF-a and IFN-g, which have been ascribed both pro-as well as antiangiogenic effects [60,61].…”

The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

“…[100][101][102][103][104][105] The activation of a leukemia-associated neoangiogenic program is instructed by proangiogenic factors released by the neoplastic cells, including VEGF, HGF, bFGF, and TNFa. [106][107][108][109] Cytokine contribution to angiogenesis in non-BCR-ABL MPN has recently been reviewed elsewhere. 110 VEGF, for instance, is highly expressed by megakaryocytes, myeloid progenitors, and granulocytes in chronic and blast crisis CML, 111 with increased levels also observed in human 66,107 and mouse models of MDS, 112 where it appears to be equally secreted by malignant and stromal niche cells.…”