Angiopoietin-1 Induces Endothelial Cell Sprouting Through the Activation of Focal Adhesion Kinase and Plasmin Secretion

Kim, Injune; Kim, Hwan Gyu; Moon, Sang-Ok; Chae, Soo Wan; So, June-No; Koh, Keum Nim; Ahn, Byung Cook; Koh, Gou Young

doi:10.1161/01.res.86.9.952

Cited by 233 publications

(198 citation statements)

References 32 publications

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“…5 Ang1 has also been shown to induce postnatal angiogenesis in a variety of experimental models. In cultured cells, Ang1 alone induced EC chemotaxis, 8,14,15,30 capillary-like tube formation 9 -11 and sprouting angiogenesis, 30 and enhanced EC survival. 11,20 In vivo reports have shown that Ang1 is unable to induce angiogenesis alone, but potentiated the angiogenic response to VEGF.…”

Section: Discussionmentioning

confidence: 98%

Angiogenic Actions of Angiopoietin-1 Require Endothelium-Derived Nitric Oxide

Babaei

Teichert-Kuliszewska

Zhang

et al. 2003

The American Journal of Pathology

163

140

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Angiopoietin1 (Ang1) is a novel angiogenic factor with important actions on endothelial cell (EC) differentiation and vascular maturation. Ang1 has been shown to prevent EC apoptosis through activation of PI3-kinase/ Akt, a pathway that is also known to activate endothelium nitric oxide synthase (eNOS). Therefore, we hypothesized that the angiogenic effects of Ang1 would also be dependent on the PI3-kinase/Akt pathway, possibly mediated by increased eNOS activity and NO release. Treatment of human umbilical vein endothelial cells with recombinant Ang1* (300 ng/ml) for 15 minutes resulted in PI3-kinase-dependent Akt phosphorylation, comparable to that observed with vascular endothelial growth factor (VEGF) (50 ng/ml), and increased NO production in a PI3-kinase/Akt-dependent manner. Capillary-like tube formation induced by Ang1* in fibrin matrix at 24 hours (differentiation index, DI: 13.74 ؎ 0.76 versus control 1.71 ؎ 0.31) was abolished in the presence of the selective PI3-kinase inhibitor, LY294002 (50 mol/L) (DI: 0.31 ؎ 0.31, P < 0.01) or the NOS inhibitor, L-NAME (3 mmol/L) (DI: 4.10 ؎ 0.59, P < 0.01). In subcutaneous Matrigel implants in vivo, addition of recombinant Ang1* or wild-type Ang1 from conditioned media of COS-1 cells transfected with a pFLAG Ang1 expression vector, induced significant neovascularization to a degree similar to VEGF. Finally, angiogenesis in vivo in response to both Ang1 and VEGF was significantly reduced in eNOS-deficient compared with wild-type mice. In summary, our results demonstrate for the first time that endothelialderived NO is required for Ang1-induced angiogenesis, and that the PI3-kinase signaling mediates the activation of eNOS and NO release in response to

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Section: Discussionmentioning

confidence: 98%

Angiogenic Actions of Angiopoietin-1 Require Endothelium-Derived Nitric Oxide

Babaei

Teichert-Kuliszewska

Zhang

et al. 2003

The American Journal of Pathology

163

140

View full text Add to dashboard Cite

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“…Angiopoietin-1 appears to potentiate the effects of VEGF in mouse corneal assays (Asahara et al, 1998). Tie-2, the receptor for this ligand, is essential for vascular development during late organogenesis (Puri et al, 1999), and has been found to mediate angiopoietin-1 induced endothelial cell migration (Kim et al, 2000). Addition of soluble tie-2 to explants attenuated tube formation, and when added with either anti-bFGF or anti-VEGF virtually negated tube formation.…”

Section: Discussionmentioning

confidence: 99%

Multiple growth factors regulate coronary embryonic vasculogenesis

Tomanek

Zheng

Peters

et al. 2001

Developmental Dynamics

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Mechanisms regulating coronary vascularization are not well understood. To test hypotheses regarding the influence of key growth factors and their interactions, we studied vascular tube formation (vasculogenesis) in collagen gels onto which quail embryonic ventricles were placed and incubated in the presence of growth factors or inhibitors. Vasculogenesis in this model is dependent on tyrosine kinase receptors, since tube formation was totally blocked by genestein. Tube formation was attenuated when anti-bFGF or anti-VEGF neutralizing antibodies were added to the medium and nearly completely inhibited when the both were added. The attenuation associated with anti-VEGF was due primarily to a decrease in assembly of endothelial cells, while that associated with bFGF was primarily due to a reduction in endothelial cells. Soluble tie-2, the receptor for angiopoietins, also had an inhibitory effect and, when added with either anti-bFGF or anti-VEGF, markedly attenuated tube formation. At optimal doses, tube formation was enhanced 6.5-fold by bFGF and 2.5-fold by VEGF over the controls. Each of these growth factors was dependent upon the other for optimal induction of tube formation, since neutralizing antibodies to one markedly reduced the potency of the other. VEGF potency was also markedly reduced when soluble tie-2 was added to the medium. Tube formation was virtually totally blocked by exogenous TGF-␤ at doses > 1 ng/ml, while neutralizing TGF-␤ antibodies enhanced tube formation 2-fold in the 30 ng-30 g range. These data provide the first documentation of multiple growth factor regulation of coronary tube formation.

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“…However, there is also evidence suggesting that Ang1 may stimulate chemotaxis, tubule formation, and vascular sprouting and hence act as a proangiogenic agent. 9,[13][14][15] In fact, transgenic mice with increased expression of Ang1 in skin under control of the keratin-14 promoter show a moderate increase in number and a large increase in diameter of dermal vessels, demonstrating that Ang1 is proangiogenic in skin. 16 Transgenic mice with increased expression of VEGF in skin showed a large increase in leaky dermal vessels, and double transgenic mice with coexpression of Ang1 and VEGF had an additive effect on angiogenesis, but the vessels did not leak spontaneously and were resistant to inflammation-induced leakage.…”

Section: Introductionmentioning

confidence: 99%