Effects of gene delivery on collateral development in chronic hypoperfusionDiverse effects of angiopoietin-1 versus vascular endothelial growth factor

Zhou, Yingbi; Stabile, Eugenio; Walker, Jill; Shou, Magang; Baffour, Richard; Yu, Zu Xi; Rott, David; Yancopouloš, George D.; Rudge, John S.; Epstein, Steve

doi:10.1016/s0735-1097(04)01112-x

Cited by 17 publications

(21 citation statements)

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“…In fact, ANG-1 has been known to potentiate the angiogenic response to VEGF [45,51] while counteracting its effect on vascular permeability [25]. Furthermore, ANG-1 was found to enhance perfusion only in the presence of increased levels of endogenous VEGF while exogenous applied VEGF failed to improve collateral blood flow in the ischemic hypoperfused tissues [52]. Therefore, vascular characteristics evoked in response to specific growth factors may explain the discrepancy observed between perfusion and vascularity in our VEGF administered group.…”

Section: Discussionmentioning

confidence: 76%

Angiopoietin-1 promotes functional neovascularization that relieves ischemia by improving regional reperfusion in a swine chronic myocardial ischemia model

Shim

Zhang

et al. 2006

J Biomed Sci

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SummaryThis study investigates the long-term angiogenic effects of ANG-1 and VEGF in a swine chronic myocardial ischemia model. Four-weeks after gradual occlusion of the left circumflex coronary artery by ameroid constrictor, animals were injected with recombinant adenoviral vectors carrying either human ANG-1 (n=9), human VEGF 165 (n=10) or empty vector (n=7) into the left ventricle free wall supplied by the constricted artery. Left ventricular perfusion in animals that received AdANG-1 (3.25±0.16 ml/min/g, p<0.05) recovered robustly 4 weeks after gene transfer while ischemia persisted in the AdVEGF (1.09±0.13 ml/min/ g) and empty vector (1.20±0.03 ml/min/g) groups. Microvascular densities in the left ventricles of animals that received AdANG-1 (19.61±1.76/0.572 mm 2 myocardial tissue, p<0.05) and AdVEGF (18.17±1.43/ 0.572 mm 2 myocardial tissue, p<0.05) were significantly higher than animals that received empty vector (13.53±0.92/0.572 mm 2 myocardial tissue) 12 weeks after gene transfer. ANG-1, but not VEGF, contributed to enhanced regional perfusion by increasing arteriolar density (1.9±0.4/0.572 mm 2 myocardial tissue vs. 0.7±0.2/0.572 mm 2 myocardial tissue, p<0.05) of large-sized (50-100 lm) arterioles. These data demonstrate that gene transfer of ANG-1 and VEGF enhances angiogenesis, but ANG-1 promotes sustained improvement of ventricular perfusion that expedites recovery of ischemic myocardium via arteriogenesis.

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Section: Discussionmentioning

confidence: 76%

Angiopoietin-1 promotes functional neovascularization that relieves ischemia by improving regional reperfusion in a swine chronic myocardial ischemia model

Shim

Zhang

et al. 2006

J Biomed Sci

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“…9,10,21,22 However, VEGF also interfered with leakiness and induced inflammation, with negative outcome on reperfusion after ischemia. 39 Similarly, Ang-2 has been shown to contribute to increased permeability and inflammation. 29 As such, and as indicated by the results of our study, the balance and dosage of growth factors must be carefully evaluated for potential clinical use.…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin-2 Impairs Revascularization After Limb Ischemia

Reiss

Droste

Heil

et al. 2007

Circulation Research

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Abstract-Angiopoietins play important roles in the formation of neovessels and complex vascular networks. Angiopoietin (Ang)-1 and Ang-2 belong to a family of growth factors that display opposing effects on the activation of Tie2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2). Endothelial Ang-2 expression is associated with vessel destabilization and regulates a balance between vascular regression and growth. To elucidate, in particular, the role of Ang-2 after arterial artery occlusion in the mouse limb, we applied a transgenic animal model with targeted Ang-2 expression in endothelial cells. We show here that restoration of blood flow in Ang-2:Tie1 transgenic mice is dramatically impaired when Ang-2 expression is induced in the vasculature. The defective restoration of perfusion in Ang-2 transgenic mice is evidenced by reduced collateral artery growth, which typically occurs to compensate for flow deficits after occlusion of the large conductance artery. Furthermore, reduced movement capacities and higher incidents of necrosis are consequently observed in the transgenic limbs as compared with controls. Mechanistically, the observed effects are attributed to defective smooth muscle cell recruitment in Ang-2 transgenic mice. Moreover, distinct Ang-2 levels in the genetically modified animals clearly correlated with the magnitude of reduced perfusion. In conclusion, our studies define Ang-2 as an important molecule for the progression of collateral artery growth and angiogenesis during ischemia and suggest precise Ang-2 dosage activities to accomplish blood vessel growth. (Circ Res. 2007;101:88-96.)Key Words: angiopoietins Ⅲ Tie2 Ⅲ collateral artery growth Ⅲ hindlimb ischemia Ⅲ angiopoietin transgenic mice M olecular events underlying the formation of new blood vessels during angiogenesis and arteriogenesis are complex and involve the coordinated interaction of numerous growth factors and their corresponding receptors. 1,2 The angiopoietin (Ang)/Tie system has been reported to be critically involved in disease progression through the activation of signaling pathways that control angiogenic remodeling. [3][4][5][6][7] Although Ang-1 and Ang-2 share similar binding affinities for the Tie2 receptor (the tyrosine kinase with immunoglobulin and epidermal growth factor [EGF] homology domain 2 receptor), they have opposing effects on receptor activation. Ang-1 induces receptor phosphorylation and contributes to blood vessel stabilization by the recruitment of periendothelial cells. 5,6 Ang-2 antagonizes the actions of Ang-1 and, depending on the presence of vascular endothelial cell growth factor (VEGF)-A, is associated with blood vessel growth or regression. 7,8 Ang-1 is constitutively expressed in normal adult tissues, whereas Ang-2 is upregulated only at sites of vascular remodeling to allow the vessel to revert to a more plastic state. 8 As such, the development of a functional vasculature requires the spatiotemporal expression of growth factors that regulate endothelial cell pro...

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“…104 Whereas C57Bl6 mice recover almost fully without any therapeutic interference, other mouse strains (eg, Balb/C) and rabbits do not. 104,109 However, genetic components responsible for these differences have not been identified. Other key parameters affecting blood flow recovery include the age of the animals (reduced in older animals) 110 and the presence of atherosclerosis or diabetes mellitus.…”

Section: Hind-limb Ischemia Models: General Considerationsmentioning

confidence: 99%

State-of-the-Art Methods for Evaluation of Angiogenesis and Tissue Vascularization

Simons¹,

Alitalo²,

Annex³

et al. 2015

Circulation Research

112

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Effects of gene delivery on collateral development in chronic hypoperfusionDiverse effects of angiopoietin-1 versus vascular endothelial growth factor

Abstract: Exogenous Ang-1 enhances perfusion in hypoperfused tissues only in the presence of increased levels of endogenous VEGF. Overexpression of VEGF, however, after causing an inflammatory response, does not improve collateral blood flow.

Cited by 17 publications

References 0 publications

Angiopoietin-1 promotes functional neovascularization that relieves ischemia by improving regional reperfusion in a swine chronic myocardial ischemia model

Angiopoietin-1 promotes functional neovascularization that relieves ischemia by improving regional reperfusion in a swine chronic myocardial ischemia model

Angiopoietin-2 Impairs Revascularization After Limb Ischemia

State-of-the-Art Methods for Evaluation of Angiogenesis and Tissue Vascularization

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