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

Das, Arup; Fanslow, William C.; Cerretti, Douglas Pat; Warren, Erin; Talarico, Nicholas; McGuire, Paul

doi:10.1097/01.lab.0000097189.79233.d8

Cited by 71 publications

(55 citation statements)

References 34 publications

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“…However, to date, no defined mechanistic experiments have been performed that unambiguously demonstrate cellular effector functions for Ang-2 that are compatible with an antagonistic mode of action towards Tie-2. Instead, increasing evidence supports the notion that long-term stimulation of cultured endothelial cells with Ang-2 exerts agonistic Tie-2-activating functions, as evidenced by Tie-2 receptor phosphorylation (Teichert-Kuliszewska et al, 2001), sprouting angiogenesis (Korff et al, 2001;Mochizuki et al, 2002;Teichert-Kuliszewska et al, 2001), increased MMP-9 expression (Das et al, 2003) and endothelial-cell survival (Kim et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

The Tie-2 ligand Angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism

Scharpfenecker¹,

Fiedler²,

Reiss³

et al. 2005

Journal of Cell Science

340

260

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The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the endothelial receptor tyrosine kinase Tie-2, which controls vascular assembly and endothelial quiescence. The largely complementary phenotypes of Ang-1-deficient mice and Ang-2-overexpressing mice have led to an antagonistic model in which Ang-1 acts as Tie-2-activating agonist and Ang-2 acts as a Tie-2-inhibiting antagonist. To date, no mechanistic equivalent of the antagonistic Ang-1/Ang-2 model has been established and the mechanisms of Ang-2 function in particular remain mysterious. We have studied the effector functions of Ang-1 and Ang-2 on quiescent endothelial cells using a three-dimensional co-culture model of endothelial cells and smooth-muscle cells. Endothelial-cell monolayer integrity in this model is dependent on Tie-2 signaling, as evidenced by detaching endothelial cells following exposure to the small molecular weight Tie-2 inhibitor A-422885.66, which cannot be overcome by exogenous Ang-1. Accordingly, exogenous Ang-2 rapidly destabilizes the endothelial layer, which can be observed within 30-60 minutes and leads to prominent endothelial-cell detachment within 4 hours. Exogenous Ang-2-mediated endothelial-cell detachment can be rescued by Ang-1, soluble Tie-2 and vascular endothelial growth factor. Similar findings were obtained in an umbilical-vein explant model. Ang-2 is mainly produced by endothelial cells and therefore acts primarily in an autocrine manner. Thus, stimulated release of endogenous Ang-2 or overexpression of Ang-2 in endothelial cells perturbs co-culture spheroid integrity, which can be rescued by exogenous Ang-1 and vascular endothelial growth factor. However, autocrine Ang-2-mediated endothelial-cell detachment cannot be blocked by soluble Tie-2. Taken together, the data demonstrate for the first time the antagonistic Ang-1/Ang-2 concept in a defined cellular model and identify Ang-2 as a rapidly acting autocrine regulator of the endothelium that acts through an internal autocrine loop mechanism.

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Section: Discussionmentioning

confidence: 99%

The Tie-2 ligand Angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism

Scharpfenecker¹,

Fiedler²,

Reiss³

et al. 2005

Journal of Cell Science

340

260

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“…In vitro, VEGF increases both expression and release of MMP-2 and MMP-9 (Lamoreaux et al, 1998;Rooprai et al, 2000;Wang and Keiser, 1998). More recently, Ang-1 have been also described to interfere with MMP-2 and MMP-9 expressions (Das et al, 2003;Kim et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…A consistent body of experimental evidence has shown that in the initial steps of angiogenesis, the matrix metalloproteinases (MMPs) play an important role in the degradation of the basal lamina and the invasion of endothelial cells (Pepper, 2001). In addition, angiogenic factors such as VEGF and Angs could regulate MMP expressions and/or activities (Das et al, 2003;Wang and Keiser, 1998). However, proteolytic enzymes such as MMPs, in particular MMP-2 and MMP-9, could contribute to BBB injury in cerebral ischemia .…”

Section: Introductionmentioning

confidence: 99%

VEGF-Induced BBB Permeability is Associated with an MMP-9 Activity Increase in Cerebral ischemia: Both Effects Decreased by ANG-1

Valable

Montaner

Bellail

et al. 2005

J Cereb Blood Flow Metab

177

125

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After cerebral ischemia, angiogenesis, by supplying for the deficient perfusion, may be a beneficial process for limiting neuronal death and promoting tissue repair. In this study, we showed that the combination of Ang-1 and vascular endothelial growth factor (VEGF) provides a more adapted therapeutic strategy than the use of VEGF alone. Indeed, we showed on a focal ischemia model that an early administration of VEGF exacerbates ischemic damage, because of its effects on bloodbrain barrier (BBB) permeability. In contrast, a coapplication of Ang-1 and VEGF leads to a significant reduction of the ischemic and edema volumes by 50% and 42%, respectively, in comparison with VEGF-treated mice. We proposed that Ang-1 blocks the BBB permeability effect of VEGF in association with a modulation of matrix metalloproteinase (MMP) activity. Indeed, we showed on both ischemic in vivo and BBB in vitro models that VEGF enhances BBB damage and MMP-9 activity and that Ang-1 counteracts both effects. However, we also showed a synergic angiogenic effect of Ang-1 and VEGF in the brain. Taken together, these results allow to propose that, in cerebral ischemia, the combination of Ang-1 and VEGF could be used early to promote the formation of mature neovessels without inducing side effects on BBB permeability.

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“…MMP-1, MMP-2, and MMP-9 are produced during EC migration and endothelial tubule formation. 22,23 We concentrated on MMP-9 activity because we previously demonstrated that VEGF stimulated MMP-9 activity in EC and smooth muscle cell cultures. 24 We found that MMP-9 activity was greatly increased in the group treated with VEGF plus Ang-2, compared with the group treated with VEGF alone, suggesting that Ang-2 may induce MMP-9 activation.…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin-2 Facilitates Vascular Endothelial Growth Factor-Induced Angiogenesis in the Mature Mouse Brain

Zhu

Lee

Shen

et al. 2005

Stroke

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Background and Purpose— A better understanding of angiogenic factors and their effects on cerebral angiogenesis is necessary for the development of effective therapeutic strategies for ischemic brain injury. Vascular endothelial growth factor (VEGF) has been shown to induce angiogenesis in the adult mouse brain. However, the function of angiopoietin-2 (Ang-2) in cerebral angiogenesis has not been clarified. The goal of this study was to identify the combined effects of VEGF and Ang-2 on cerebral angiogenesis and the blood–brain barrier (BBB). Methods— Six groups of 6 adult male CD-1 mice underwent AdlacZ (viral vector control), AdVEGF, AdAng2, VEGF protein, VEGF protein plus AdAng2, or saline (negative control) injection. Microvessels were counted using lectin staining on tissue sections after 2 weeks of treatment. Matrix metalloproteinase-9 (MMP-9) activity was determined by zymography. The presence of zonula occludens-1 (ZO-1) protein was determined by Western blot and immunohistochemistry. Results— Mice treated with VEGF protein infusion plus AdAng-2 significantly increased microvessel counts relative to all other groups ( P <0.05). The changes in MMP-9 activity paralleled the reduced ZO-1 expression in the VEGF plus Ang-2–treated group compared with the other 5 groups ( P <0.05). Double-labeled immunostaining demonstrated that ZO-1–positive staining was significantly decreased on the microvessel wall in the VEGF plus Ang-2–treated group. Conclusions— Our study demonstrates that the combination of VEGF and Ang-2 promotes more angiogenesis compared with VEGF alone. Furthermore, the combination of VEGF and Ang-2 may lead to BBB disruption because it increases MMP-9 activity and inhibits ZO-1 expression.

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

Cited by 71 publications

References 34 publications

The Tie-2 ligand Angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism

The Tie-2 ligand Angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism

VEGF-Induced BBB Permeability is Associated with an MMP-9 Activity Increase in Cerebral ischemia: Both Effects Decreased by ANG-1

Angiopoietin-2 Facilitates Vascular Endothelial Growth Factor-Induced Angiogenesis in the Mature Mouse Brain

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