Systemically Expressed Soluble Tie2 Inhibits Intraocular Neovascularization

Hangai, Masanori; Moon, Yuen Sung; Kitaya, Norihiko; Chan, Candy King-Chi; Wu, Da-Yu; Peters, Kevin G.; Ryan, Stephen J.; Hinton, David R.

doi:10.1089/104303401750270968

Cited by 68 publications

(40 citation statements)

References 41 publications

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“…54 Furthermore, inhibition of the Tie2 receptor with adenovirus-mediated gene delivery also attenuates angiogenesis in mouse models of ROP and choroidal neovascularization. 55 The findings of the present study support an angiogenic role for Ang2 and Tie2 as both were increased with ROP in the setting of elevated VEGF, whereas Ang1 mRNA remained unchanged. In ROP, the stimulus for up-regulation of VEGF is tissue hypoxia, 7,25,48 which may also be the case for Ang2 and Tie2 as initially observed in rat glioma cells and BRECs.…”

Section: Discussionsupporting

confidence: 80%

Retinal Angiogenesis Is Mediated by an Interaction between the Angiotensin Type 2 Receptor, VEGF, and Angiopoietin

Sarlos

Rizkalla

Moravski

et al. 2003

The American Journal of Pathology

131

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There is evidence that angiotensin II, vascular endothelial growth factor (VEGF), angiopoietins, and their cognate receptors participate in retinal angiogenesis. We investigated whether angiotensin type 2-receptor blockade (AT2-RB) reduces retinal angiogenesis and alters the expression of VEGF/VEGF-R2 and angiopoietin-Tie2. Retinopathy of prematurity (ROP) was induced in Sprague Dawley (SD) rats by exposure to 80% oxygen from postnatal (P) days 0 to 11, followed by 7 days in room air. ROP shams were in room air from P0 -18. A group of ROP rats received the AT2-RB, PD123319, by mini-osmotic pump (5 mg/kg/day) from P11-18 (angiogenesis period). Evaluation of the retinal status of the AT2 receptor indicated that this receptor, as assessed by real-time PCR, immunohistochemistry, and in vitro autoradiography, was present in the retina, was more abundant than the AT1 receptor in the neonatal retina, and was increased in the ROP model. AT2-RB reduced retinal angiogenesis. VEGF and VEGF-R2 mRNA were increased in ROP and localized to blood vessels, ganglion cells, and the inner nuclear layer, and were decreased by PD123319. Angiopoietin2 and Tie2, but not angiopoietin1 mRNA were increased with ROP, and angiopoietin2 was reduced with PD123319. This study has identified a potential retinoprotective role for AT2-RB possibly mediated via interactions with VEGF-and angiopoietin-dependent pathways.

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Section: Discussionsupporting

confidence: 80%

Retinal Angiogenesis Is Mediated by an Interaction between the Angiotensin Type 2 Receptor, VEGF, and Angiopoietin

Sarlos

Rizkalla

Moravski

et al. 2003

The American Journal of Pathology

131

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“…However, emerging evidence suggests that additional signaling of ANG-1 and ANG-2 through integrin receptors may be important in their diverse contribution toward tumor growth. The existence of various ligands (ANG-1, ANG-2, and ANG-4), their isoforms [four ANG-1 isoforms (31) and two ANG-2 isoforms (125)], and soluble forms of TIE-1 and TIE-2 receptors (126, 127) and TIE-2/TIE-1 heterodimerization in modulating receptivity (73) and differential induction of both receptors and ligands (119,128,129) compounded the difficulty of precise definition of the role of the ANGs during angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin: A TIE(d) Balance in Tumor Angiogenesis

Shim

Wong

2007

Molecular Cancer Research

152

111

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Angiopoietins (ANG-1 and ANG-2) and their TIE-2 receptor tyrosine kinase have wide-ranging effects on tumor malignancy that includes angiogenesis, inflammation, and vascular extravasation. These multifaceted pathways present a valuable opportunity in developing novel inhibition strategies for cancer treatment. However, the regulatory role of ANG-1 and ANG-2 in tumor angiogenesis remains controversial. There is a complex interplay between complementary yet conflicting roles of both the ANGs in shaping the outcome of angiogenesis. Embryonic vascular development suggests that ANG-1 is crucial in engaging interaction between endothelial and perivascular cells. However, recruitment of perivascular cells by ANG-1 has recently been implicated in its antiangiogenic effect on tumor growth. It is becoming clear that TIE-2 signaling may function in a paracrine and autocrine manner directly on tumor cells because the receptor has been increasingly found in tumor cells. In addition, A 5 B 1 and A v B 5 integrins were recently recognized as functional receptors for ANG-1 and ANG-2. Therefore, both the ligands may have wide-ranging functions in cellular activities that affect overall tumor development. Collectively, these TIE-2 -dependent and TIE-2 -independent activities may account for the conflicting findings of ANG-1 and ANG-2 in tumor angiogenesis. These uncertainties have impeded development of a clear strategy to target this important angiogenic pathway. A better understanding of the molecular basis of ANG-1 and ANG-2 activity in the pathophysiologic regulation of angiogenesis may set the stage for novel therapy targeting this pathway. (Mol Cancer Res 2007;5(7):655 -65)

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“…The mice showed no side effects related to the treatment, nor was there evidence of toxicity within the retinal tissues. Previous studies have employed either an im injection of an adenovirus expressing the extracellular domain of the Tek/Tie 2 receptor (Hangai et al, 2001) or an intraocular injection of a soluble Tie-2 receptor/Fc fusion protein similar to the one used in the present study. Results from these studies have demonstrated a similar although significantly lower degree of inhibition (47% and 23%, respectively) of retinal neovascularization in the same mouse model.…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin/Tek Interactions Regulate MMP-9 Expression and Retinal Neovascularization

Das

Fanslow

Cerretti

et al. 2003

Laboratory Investigation

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SUMMARY:The objective of the study was to determine the role of the angiopoietins in the regulation of gelatinase expression during angiogenesis, and whether inhibition of the angiopoietin/Tek interaction in vivo can suppress the extent of retinal neovascularization. Retinal microvascular endothelial cells were treated with angiopoietins and examined for the production of gelatinases. The effects of inhibiting angiopoietin binding to the Tie-2 receptor was studied in newborn mice with experimentally induced retinal neovascularization. Animals were treated with an ip injection of the Tie-2 antagonist, muTek delta Fc, while oxygen-exposed mice treated with similar concentrations of murine IgG were used as controls. The effect of muTek delta Fc on the gelatinase expression in the retina was examined by real-time RT-PCR analysis. The stimulation of cultured retinal endothelial cells with Ang-1 and -2 resulted in the increased expression of matrix metalloproteinase (MMP)-9. Ang-2 expression was up-regulated in experimental animals during the period of angiogenesis and was the greatest on Day 17 (the time of maximal angiogenic response). Histologic analysis of mice treated with the Tie-2 antagonist, muTek delta Fc, showed significant (87%; p ϭ 0.001) inhibition of retinal neovascularization, and the response was dose-dependent. In vitro binding data support the fact that both Ang-1 and Ang-2 bind with high avidity to muTek delta Fc. The RT-PCR analysis of the retinas of the Tek-treated animals showed a similar (80%; p ϭ 0.001) inhibition of the MMP-9 expression, which correlated with the decrease in angiogenesis. The up-regulation of gelatinases in microvascular endothelial cells by Ang-2 may be an important early response during the development of retinal neovascularization. Inhibition of the binding activity of the angiopoietins in vivo suppressed retinal neovascularization concomitant with a reduction in the expression of MMP-9. (Lab Invest 2003, 83:1637-1645.

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Systemically Expressed Soluble Tie2 Inhibits Intraocular Neovascularization

Cited by 68 publications

References 41 publications

Retinal Angiogenesis Is Mediated by an Interaction between the Angiotensin Type 2 Receptor, VEGF, and Angiopoietin

Retinal Angiogenesis Is Mediated by an Interaction between the Angiotensin Type 2 Receptor, VEGF, and Angiopoietin

Angiopoietin: A TIE(d) Balance in Tumor Angiogenesis

Angiopoietin/Tek Interactions Regulate MMP-9 Expression and Retinal Neovascularization

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