Angiopoietin‐2 plays an important role in retinal angiogenesis

Hackett, Sean F.; Wiegand, Stanley J.; Yancopouloš, George D.; Campochiaro, Peter A.

doi:10.1002/jcp.10128

Cited by 177 publications

(132 citation statements)

References 30 publications

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“…9 Although VEGF expression has been well characterized in this model for C57BL/6J mice, 32 the biphasic pattern of VEGF expression observed in this study for both inbred strains, has not been reported and may represent an initial hypoxia-induced peak of VEGF expression followed by a decline in mRNA levels due to receptor-activated negative feedback. 34 The initial peak in VEGF expression may be associated with increased vascular congestion and dilatation observed in the retina in this model prior to onset of angiogenesis. 26 The second increase observed in VEGF expression following 48 h, may be associated with initiation of angiogenesis in response to prolonged hypoxia.…”

Section: Discussionmentioning

confidence: 78%

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Differential expression of pro- and antiangiogenic factors in mouse strain-dependent hypoxia-induced retinal neovascularization

Chan

Pham

Zhou

et al. 2005

Laboratory Investigation

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Clinical observations suggest that genetic factors may influence heterogeneity of angiogenic responses in cardiovascular disease, proliferative diabetic retinopathy, and neoplasia. Experiments among mouse strains using a corneal micropocket assay indicate that extent of angiogenesis may be genetically determined. Here, we established the strain-dependence of hypoxia-induced retinal angiogenesis in multiple mouse strains which paralleled the rank order found for bFGF-induced corneal angiogenesis. Using quantitative real-time RT-PCR, strain-related gene expression differences in retina/choroid between C57BL/6J and 129S3/SvIM, inbred strains with relatively low and high levels of angiogenesis, respectively, after 0, 6, 12, 24, 48, and 96 h hypoxia were determined for vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), angiogenic ligands potently induced by hypoxia, and for pigment epithelium-derived factor (PEDF) and thrombospondin-1 (TSP-1), endogenous broad-spectrum antiangiogenic factors. Indirect ELISA was used to correlate VEGF and PEDF protein levels with mRNA expression. At the onset of hypoxia, both PEDF and TSP-1 levels were increased over 15-fold and VEGF was increased over 10-fold compared to Ang-2 in both strains. At the onset of neovascularization (48 h), both VEGF and Ang-2 mRNA levels were increased in the more angiogenic 129S3/ SvIM strain (Po0.02), which was not observed among developmental control animals. PEDF expression was higher in the less angiogenic C57BL/6J strain at 6, 12, 24, and 96 h hypoxia (Po0.03), while TSP-1 expression was higher in C57BL/6J throughout the entire time course of hypoxia (4 days) compared to 129S3/SvIM (Po0.02). Among developmental control animals, PEDF and TSP-1 expression was also increased at P14 and P16 in C57BL/6J strain compared to 129S3/SvIM (Po0.02). Strain-dependent expression of both pro-and antiangiogenic growth factors may determine heterogeneity in the angiogenic response and potentially, susceptibility to angiogenesis-dependent diseases.

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Section: Discussionmentioning

confidence: 78%

“…33,34 Ang-2 mRNA levels were slightly (but significantly) increased in the more angiogenic 129S3/SvIM strain at 48 h compared to C57BL/6J (Po0.03). In addition, the relative increase in Ang-2 expression between 48 and 96 h, suggests an increased need for Ang-2 during the growth phase of angiogenesis.…”

Section: Discussionmentioning

confidence: 89%

Differential expression of pro- and antiangiogenic factors in mouse strain-dependent hypoxia-induced retinal neovascularization

Chan

Pham

Zhou

et al. 2005

Laboratory Investigation

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“…Previous studies have shown that vascular endothelial cells are the primary source of Ang2 (32)(33)(34)(35). High glucose increases Ang2 mRNA in HRMECs (36).…”

Section: Discussionmentioning

confidence: 98%

Angiopoietin 2 Induces Pericyte Apoptosis via α3β1 Integrin Signaling in Diabetic Retinopathy

et al. 2014

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Pericyte loss is an early characteristic change in diabetic retinopathy (DR). Despite accumulating evidence that hyperglycemia-induced angiopoietin 2 (Ang2) has a central role in pericyte loss, the precise molecular mechanism has not been elucidated. This study investigated the role of Ang2 in pericyte loss in DR. We demonstrated that pericyte loss occurred with Ang2 increase in the diabetic mouse retina and that the source of Ang2 could be the endothelial cell. Ang2 induced pericyte apoptosis via the p53 pathway under high glucose, whereas Ang2 alone did not induce apoptosis. Integrin, not Tie-2 receptor, was involved for Ang2-induced pericyte apoptosis under high glucose as an Ang2 receptor. High glucose changed the integrin expression pattern, which increased integrin α3 and β1 in the pericyte. Furthermore, Ang2-induced pericyte apoptosis in vitro was effectively attenuated via p53 suppression by blocking integrin α3 and β1. Although intravitreal injection of Ang2 induced pericyte loss in C57BL/6J mice retina in vivo, intravitreal injection of anti-integrin α3 and β1 antibodies attenuated Ang2-induced pericyte loss. Taken together, Ang2 induced pericyte apoptosis under high glucose via α3β1 integrin. Glycemic control or blocking Ang2/integrin signaling could be a potential therapeutic target to prevent pericyte loss in early DR.

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“…In certain settings, Ang-2 triggers EC Tie-2 phosphorylation, enhancing vessel growth; [33][34][35] second, Ang-2 null mutant mice have disordered lymphatics because Ang-2 stimulates lymphatic capillary maturation; 20 and third, Ang-2 can support EC adhesion independently from Tie-2 signaling. 36 Ang-2 modulates remodeling of ocular blood capillaries 20,37 but its possible functions in differentiation of other organs is unknown. Tie-2, and its Ang-1 and Ang-2 ligands, are expressed in the mouse metanephros and in the mature organ, with total levels peaking in perinatally.…”

mentioning

confidence: 99%

Dysmorphogenesis of Kidney Cortical Peritubular Capillaries in Angiopoietin-2-Deficient Mice

Pitera¹,

Woolf²,

Gale³

et al. 2004

The American Journal of Pathology

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Angiopoietin-2 (Ang-2) modulates Tie-2 receptor activation. In mouse kidney maturation, Ang-2 is expressed in arteries, with lower levels in tubules, whereas Tie-2 is expressed by endothelia. We hypothesized that Ang-2 deficiency disrupts kidney vessel patterning. The normal renal cortical peritubular space contains fenestrated capillaries, which have few pericytes; they receive water and solutes which proximal tubules reclaim from the glomerular filtrate. In wild-type neonates, ␣ smooth muscle actin (␣SMA), platelet-derived growth factor receptor ␤ (PDGFR␤), and desmin-expressing cells were not prominent in this compartment. In Ang-2 null mutants, ␣SMA, desmin, and PDGFR␤ prominently immunolocalized in cortical peritubular locations. Some ␣SMA-positive cells were closely associated with CD31-and Tie-2-positive peritubular capillary endothelia, and some of the ␣SMA-positive cells expressed PDGFR␤, desmin, and neural/glial cell 2 (NG2), consistent with a pericyte-like identity. Immunoblotting suggested an increase of total and tyrosine-phosphorylated Tie-2 proteins in null mutant versus wild-type kidneys, and electron microscopy confirmed disorganized capillaries and adjacent cells in cortical peritubular spaces in mutant neonate kidneys. Hence, Ang-2 deficiency causes dysmorphogenesis of cortical peritubular capillaries, with adjacent cells expressing pericyte-like markers; we speculate the latter effect is caused by disturbed paracrine signaling between endothelial and surrounding mesenchymal precursor cells.

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Angiopoietin‐2 plays an important role in retinal angiogenesis

Cited by 177 publications

References 30 publications

Differential expression of pro- and antiangiogenic factors in mouse strain-dependent hypoxia-induced retinal neovascularization

Differential expression of pro- and antiangiogenic factors in mouse strain-dependent hypoxia-induced retinal neovascularization

Angiopoietin 2 Induces Pericyte Apoptosis via α3β1 Integrin Signaling in Diabetic Retinopathy

Dysmorphogenesis of Kidney Cortical Peritubular Capillaries in Angiopoietin-2-Deficient Mice

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