Angiopoietin-2 at high concentration can enhance endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway

Kim, Injune; Kim, Jihye; Moon, Sang-Ok; Kwak, Hee Jin; Kim, Nam-Gyun; Koh, Gou Young

doi:10.1038/sj.onc.1203800

Cited by 290 publications

(215 citation statements)

References 27 publications

Supporting

Mentioning

202

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, we found that continuous IFN-h delivery also augmented angiopoietin-2 expression in treated xenografts of one of the cell lines. Although angiopoietin-2 is reported to be an antagonist of angiopoietin-1 by preventing angiopoietin-1-mediated activation of the Tie2 receptor (25), several studies have shown that angiopoietin-2 can, in certain circumstances, actually activate Tie2 (36,37). Because the soluble, truncated Tie2 receptor used in our studies binds both angiopoietin-1 and angiopoietin-2, we were not able to further define their relative contributions to the vascular maturation achieved with continuous IFN-h.…”

Section: Discussionmentioning

confidence: 59%

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Dickson¹,

Hamner²,

Streck³

et al. 2007

Molecular Cancer Research

View full text Add to dashboard Cite

IFNs have pleiotropic antitumor mechanisms of action. The purpose of this study was to further investigate the effects of IFN-B on the vasculature of human xenografts in immunodeficient mice. We found that continuous, systemic IFN-B delivery, established with liver-targeted adeno-associated virus vectors, led to sustained morphologic and functional changes of the tumor vasculature that were consistent with vessel maturation. These changes included increased smooth muscle cell coverage of tumor vessels, improved intratumoral blood flow, and decreased vessel permeability, tumor interstitial pressure, and intratumoral hypoxia. Although these changes in the tumor vasculature resulted in more efficient tumor perfusion, further tumor growth was restricted, as the mature vasculature seemed to be unable to expand to support further tumor growth. In addition, maturation of the intratumoral vasculature resulted in increased intratumoral penetration of systemically administered chemotherapy. Finally, molecular analysis revealed increased expression by treated tumors of angiopoietin-1, a cytokine known to promote vessel stabilization. Induction of angiopoietin-1 expression in response to IFN-B was broadly observed in different tumor lines but not in those with defects in IFN signaling. In addition, IFN-B -mediated vascular changes were prevented when angiopoietin signaling was blocked with a decoy receptor. Thus, we have identified an alternative approach for achieving sustained vascular remodeling-continuous delivery of IFN-B. In addition to restricting tumor growth by inhibiting further angiogenesis, maturation of the tumor vasculature also improved the efficiency of delivery of adjuvant therapy. These results have significant implications for the planning of combination anticancer therapy.

show abstract

Section: Discussionmentioning

confidence: 59%

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Dickson¹,

Hamner²,

Streck³

et al. 2007

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…In early reports, Angio2 has been shown to antagonize Angio1-mediated Tie2 activation; however, when Tie2 was ectopically transfected, Angio2 induced Tie2 activation. 35 Moreover, the observations that high concentrations of Angio2 enhances EC survival and stimulates migration and tube-like structure formation 36,44 raise the possibility that rather than acting as an antagonist of Angio1, Angio2 can sustain an active role in Tie2-mediated signaling. Signal transduction pathways via Tie2 have been extensively examined; 10,11,36,44 -46 however, in many studies Tie2 was activated in a ligand-independent manner or by high concentrations of Angio2.…”

Section: Discussionmentioning

confidence: 99%

“…This study shows that Tie2 engagement by Angio1 or Angio2 in EC activates discrete signaling pathways and that physiological or high concentrations of Angio2 can elicit STAT5 activation to control cell growth or Akt phosphorylation to control cell survival, respectively. 36 We previously reported that the activated STAT5 and p21 waf were almost exclusively expressed in neovessels of advanced lesions. 19 Herein we demonstrate that, in contrast with NF B, which is also expressed in early lesions, 47 a positive immunostaining for the activated STAT5 could be detected only in EC of advanced lesions.…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin 2 Induces Cell Cycle Arrest in Endothelial Cells: A Possible Mechanism Involved in Advanced Plaque Neovascularization

Calvi

Dentelli

Pagano

et al. 2004

ATVB

View full text Add to dashboard Cite

Objective-To characterize the molecules and the mechanisms regulating the neoangiogenetic process in advanced atherosclerotic plaques. Methods and Results-Western blot and immunofluorescence analysis of atherosclerotic specimens demonstrated that unlike neovessels from early lesions that expressed vascular endothelial growth factor (VEGF) and angiopoietin1 (Angio1), vessels from advanced lesions expressed VEGF and angiopoietin 2 (Angio2). Moreover, only few neovessels from advanced lesions showed a positive immunostaining for proliferating cell nuclear antigen. Angio1-elicited and Angio2-elicited intracellular events in endothelial cells (EC) demonstrated that while Angio1 triggered Erk1/Erk2 mitogen activated protein kinases (MAPK) and Akt activation, Angio2 (50 ng/mL) induced STAT5 activation and p21 waf expression and increased the fraction of cells in G1. Both Angio2-mediated events were abrogated by expressing a dominant negative STAT5 construct (⌬STAT5). Consistent with the expression of Angio2 in neovessels of advanced lesions a transcriptionally active STAT5 was detected. Moreover, co-immunoprecipitation experiments revealed the presence of a STAT5/Tie2 molecular complex in neointima vessels from advanced, but not from early, lesions. 3 Consistently, in vivo developing primary lesions might be considered as underperfused and dependent on neovessel formation for continued growth. 4 Angiogenesis in mature tissues is composed of a series of cellular responses including activation of EC proliferation by angiogenic factors, such as VEGF, fibroblast growth factor (FGF), and angiopoietins (Angio) and formation of tube-like structures and vessel stabilization. 5 Compared with the developmental angiogenesis, the role of angiopoietins in pathological angiogenesis is less understood. The angiopoietin family consists of four members, Angio1 to 4. 6 -8 Angio1 and 4 stimulate their receptor tyrosine kinase Tie2, whereas Angio2 and 3 by binding to Tie2 antagonize Angio1 signaling. 6 -8 Signal transduction pathways via Tie2 and VEGF receptors (VEGFR) have been extensively examined. 9,10 In particular, Korpelainem et al showed that Tie2 and VEGFR1 overexpression triggers the phosphorylation of the signal transducer and activator of transcription (STAT) 3 and STAT5. 11 STAT5 belongs to the family of transcriptional factors, which, on activation, binds to the receptor via their src homology 2 domain (SH2). 12 Recruited STATs, dimerize, translocate to the nucleus, and activate transcription of target genes mainly involved in regulation of cell cycle progression. 12,13 Cell cycle phases are coordinated by regulatory proteins denoted as cyclins and cyclin-dependent kinases (CDKs). 14 Phase-specific cyclin/CDK complexes confer specificity and orderly progression through the cell cycle. Initially, cyclin D/CDK4 or cyclin E/CDK2 complexes, in cooperation with proliferating cell nuclear antigen (PCNA), coordinate DNA duplication by regulating the transition through the G1 and S phase. 15 Furthermore, cell cycle progression is ...

show abstract

“…More recently, other Ang-2 actions were discovered. In certain settings, Ang-2 triggers EC Tie-2 phosphorylation, enhancing vessel growth; [33][34][35] second, Ang-2 null mutant mice have disordered lymphatics because Ang-2 stimulates lymphatic capillary maturation; 20 and third, Ang-2 can support EC adhesion independently from Tie-2 signaling. 36 Ang-2 modulates remodeling of ocular blood capillaries 20,37 but its possible functions in differentiation of other organs is unknown.…”

mentioning

confidence: 99%

Dysmorphogenesis of Kidney Cortical Peritubular Capillaries in Angiopoietin-2-Deficient Mice

Pitera¹,

Woolf²,

Gale³

et al. 2004

The American Journal of Pathology

View full text Add to dashboard Cite

Angiopoietin-2 (Ang-2) modulates Tie-2 receptor activation. In mouse kidney maturation, Ang-2 is expressed in arteries, with lower levels in tubules, whereas Tie-2 is expressed by endothelia. We hypothesized that Ang-2 deficiency disrupts kidney vessel patterning. The normal renal cortical peritubular space contains fenestrated capillaries, which have few pericytes; they receive water and solutes which proximal tubules reclaim from the glomerular filtrate. In wild-type neonates, ␣ smooth muscle actin (␣SMA), platelet-derived growth factor receptor ␤ (PDGFR␤), and desmin-expressing cells were not prominent in this compartment. In Ang-2 null mutants, ␣SMA, desmin, and PDGFR␤ prominently immunolocalized in cortical peritubular locations. Some ␣SMA-positive cells were closely associated with CD31-and Tie-2-positive peritubular capillary endothelia, and some of the ␣SMA-positive cells expressed PDGFR␤, desmin, and neural/glial cell 2 (NG2), consistent with a pericyte-like identity. Immunoblotting suggested an increase of total and tyrosine-phosphorylated Tie-2 proteins in null mutant versus wild-type kidneys, and electron microscopy confirmed disorganized capillaries and adjacent cells in cortical peritubular spaces in mutant neonate kidneys. Hence, Ang-2 deficiency causes dysmorphogenesis of cortical peritubular capillaries, with adjacent cells expressing pericyte-like markers; we speculate the latter effect is caused by disturbed paracrine signaling between endothelial and surrounding mesenchymal precursor cells.

show abstract

Angiopoietin-2 at high concentration can enhance endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway

Cited by 290 publications

References 27 publications

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Angiopoietin 2 Induces Cell Cycle Arrest in Endothelial Cells: A Possible Mechanism Involved in Advanced Plaque Neovascularization

Dysmorphogenesis of Kidney Cortical Peritubular Capillaries in Angiopoietin-2-Deficient Mice

Contact Info

Product

Resources

About