Direct Intramuscular Injection of Plasmid DNA Encoding Angiopoietin-1 but not Angiopoietin-2 Augments Revascularization in the Rabbit Ischemic Hindlimb

Shyu, Kou‐Gi; Manor, Orit; Magner, Meredith; Yancopouloš, George D.; Isner, Jeffrey M.

doi:10.1161/01.cir.98.19.2081

Cited by 170 publications

(113 citation statements)

References 38 publications

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“…These results are consistent with previous reports showing Ang1-induced angiogenesis in the absence of exogenous VEGF. 34,35 The reason for the variable requirement for VEGF in these models is unclear, but may relate to differences in its endogenous expression of growth factors. Since Ang1 does not directly induce EC proliferation, 6,9,31 the action of an additional EC mitogen such as VEGF may be crucial in facilitating the angiogenic effects of Ang1.…”

Section: Discussionmentioning

confidence: 99%

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

Babaei

Teichert-Kuliszewska

Zhang

et al. 2003

The American Journal of Pathology

164

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: 99%

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

Babaei

Teichert-Kuliszewska

Zhang

et al. 2003

The American Journal of Pathology

164

140

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“…Animal and clinical data indicated that angiogenic factors such as fibroblast growth factor (1-3), VEGF (4-7), angiopoietins (8), and hepatocyte growth factor (9,10) can induce angiogenesis in ischemic myocardium and improve cardiac function of MI heart. VEGF and angiopoietin-1 (Ang1) can also activate a prosurvival signaling pathway and attract stem cell homing (11).…”

mentioning

confidence: 99%

Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart

Zeng

Chen

Tan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

156

103

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VEGF and angiopoietin-1 (Ang1) are two major angiogenic factors being investigated for the treatment of myocardial infarction (MI). Targeting VEGF and Ang1 expression in the ischemic myocardium can increase their local therapeutic effects and reduce possible adverse effects. Adeno-associated viral vectors (AAVs) expressing cardiac-specific and hypoxia-inducible VEGF [AAV-myosin light chain-2v (MLC)VEGF] and Ang1 (AAV-MLCAng1) were coinjected (VEGF/Ang1 group) into six different sites of the porcine myocardium at the peri-infarct zone immediately after ligating the left descending coronary artery. An identical dose of AAV-Cytomegalovirus (CMV)LacZ or saline was injected into control animals. AAV genomes were detected in the liver in addition to the heart. RT-PCR, Western blotting, and ELISA analyses showed that VEGF and Ang1 were predominantly expressed in the myocardium in the infarct core and border of the infarct heart. Gated single-photon emission computed tomography analyses showed that the VEGF/Ang1 group had better cardiac function and myocardial perfusion at 8 wk than at 2 wk after vector injection. Compared with the saline and LacZ controls, the VEGF/Ang1 group expressed higher phosphorylated Akt and Bcl-xL, less Caspase-3 and Bad, and had higher vascular density, more proliferating cardiomyocytes, and less apoptotic cells in the infarct and peri-infarct zones. Thus, cardiac-specific and hypoxia-induced coexpression of VEGF and Ang1 improves the perfusion and function of porcine MI heart through the induction of angiogenesis and cardiomyocyte proliferation, activation of prosurvival pathways, and reduction of cell apoptosis.

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“…In adult, endothelial cells from di erent areas have di erent characteristics themselves and their responses to growth factors are di erent (Risau, 1995). Transgenic overexpression or gene transfer of Ang1 increases vascularization (Suri et al, 1998;Shyu et al, 1998) and decreases vascular leakage in vivo (Thurston et al, 1999(Thurston et al, , 2000. However, gene transfer of Ang2 does not produce signi®cant vascularization in ischemic limbs (Shyu et al, 1998).…”

mentioning

confidence: 99%

“…Transgenic overexpression or gene transfer of Ang1 increases vascularization (Suri et al, 1998;Shyu et al, 1998) and decreases vascular leakage in vivo (Thurston et al, 1999(Thurston et al, , 2000. However, gene transfer of Ang2 does not produce signi®cant vascularization in ischemic limbs (Shyu et al, 1998). In a mouse corneal micropocket assay, both Ang1 and Ang2 failed to stimulate an angiogenic response when administered alone (Asahara et al, 1998).…”

mentioning

confidence: 99%