Angiopoietin-2 Causes Inflammation in Vivo by Promoting Vascular Leakage

Roviezzo, Fiorentina; Tsigkos, Stelios; Κοτανίδου, Αναστασία; Bucci, Mariarosaria; Brancaleone, Vincenzo; Cirino, Giuseppe; Papapetropoulos, Andreas

doi:10.1124/jpet.105.086553

Cited by 208 publications

(158 citation statements)

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“…13 The release of Ang2 resulted in rapid destabilization of the endothelium and triggered an inflammatory response. [13][14][15] A recent study has highlighted Ang2 as having a critical role in animal models of hyperoxia-induced lung injury and inflammation. 12 Ang2 caused increased inflammation and cell death in the lung on exposure to hyperoxia.…”

Section: Introductionmentioning

confidence: 99%

Angiopoietin 2 concentrations in infants developing bronchopulmonary dysplasia: attenuation by dexamethasone

et al. 2007

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Objectives: To study the association between angiopoietin 2 (Ang2) concentrations in tracheal aspirates (TAs) and adverse outcome (bronchopulmonary dysplasia (BPD)/death) in ventilated premature infants (VPIs) and modulation of Ang2 concentrations with dexamethasone (Dex) use.Study Design: Serial TA samples were collected on days 1, 3, 5 and 7, and Ang2 concentrations were measured. Ang2 TA concentrations were compared prior to and after 48 to 72 h of using Dex.Result: A total of 151 TA samples were collected from 60 VPIs. BPD was defined as the oxygen requirement at 36 weeks postmenstrual age (PMA). Twelve infants (mean ± s.d.) (gestational age (GA) 26.5 ± 2.1 weeks, birth weight (BW) 913±230 g) had no BPD, 32 infants (GA 25.8±1.4 weeks, BW 768 ± 157 g) developed BPD and 16 infants (GA 24.5 ± 1.1 weeks, BW 710 ± 143 g) died before 36 weeks PMA. Ang2 concentrations were significantly lower in infants with no BPD (median, 25th and 75th percentile) (157, 16 and 218 pg mg À1 ) compared with those who developed BPD (234, 138 and 338 pg mg À1 , P ¼ 0.03) or BPD and/or death (234, 157 and 347 pg mg À1 , P ¼ 0.017), in the first week of life. Twenty-six VPIs (BW 719±136 g, GA 25.1±1.3 weeks) received 27 courses of Dex. Ang2 concentrations before starting Dex were 202, 137 and 278 pg mg À1 and significantly decreased to 144, 0 and 224 pg mg À1 after therapy (P ¼ 0.007).Conclusions: Higher Ang2 concentrations in TAs are associated with the development of BPD or death in VPIs. Dex use suppressed Ang2 concentrations.

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Section: Introductionmentioning

confidence: 99%

Angiopoietin 2 concentrations in infants developing bronchopulmonary dysplasia: attenuation by dexamethasone

et al. 2007

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“…Animals were killed 3, 5, and 7 d after stroke (n ϭ 3, each time point), and their brains were frozen and processed for the presence of biotin-labeled protein using Alexa488-conjugated streptavidin (Invitrogen). For gainand loss-of-function experiments, osmotic minipumps were filled with low and high doses of recombinant Ang1 (0.05 g/100 l and 0.5 g/100 l), receptor-blocking anti-mouse Tie2 antibody (1 g/100 l and 10 g/100 l), recombinant SDF1␤ (0.27 g/100 l and 2.7 g/100 l), and the CXCR4 receptor antagonist AMD3100 (1.5 mg/100 l and 5 mg/100 l; gift from Dr. Edward Hoover, Colorado State University, Fort Collins, CO), based on published results (Witzenbichler et al, 1998;Herodin et al, 2003;Roviezzo et al, 2005). Control stroke and sham animals received vehicle (0.1 M NaPBS, pH 7.4).…”

Section: Neurovascular Ligand Gain-and Loss-of-function Experimentsmentioning

confidence: 99%

A Neurovascular Niche for Neurogenesis after Stroke

Ohab¹,

Fleming²,

Blesch³

et al. 2006

J. Neurosci.

792

783

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Stroke causes cell death but also birth and migration of new neurons within sites of ischemic damage. The cellular environment that induces neuronal regeneration and migration after stroke has not been defined. We have used a model of long-distance migration of newly born neurons from the subventricular zone to cortex after stroke to define the cellular cues that induce neuronal regeneration after CNS injury. Mitotic, genetic, and viral labeling and chemokine/growth factor gain-and loss-of-function studies show that stroke induces neurogenesis from a GFAP-expressing progenitor cell in the subventricular zone and migration of newly born neurons into a unique neurovascular niche in peri-infarct cortex. Within this neurovascular niche, newly born, immature neurons closely associate with the remodeling vasculature. Neurogenesis and angiogenesis are causally linked through vascular production of stromal-derived factor 1 (SDF1) and angiopoietin 1 (Ang1). Furthermore, SDF1 and Ang1 promote post-stroke neuroblast migration and behavioral recovery. These experiments define a novel brain environment for neuronal regeneration after stroke and identify molecular mechanisms that are shared between angiogenesis and neurogenesis during functional recovery from brain injury.

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“…Ang-1 is an oligomeric-secreted glycoprotein that binds to the Tie-2 receptor and induces Tie-2 phosphorylation (3)(4)(5). Accumulating data demonstrate that dominant Ang-1/Tie-2 signaling is essential for the maintenance of endothelial integrity and vessel maturation (3,(5)(6)(7)(8)(9)(10). VEGF is required to initiate immature vascular formation, whereas Ang-1 is required for further remodeling and maturation of VEGFinitiated immature vessels during postischemic angiogenesis (1,2).…”

mentioning

confidence: 99%

Ang-1 Gene Therapy Inhibits Hypoxia-Inducible Factor-1α (HIF-1α)-Prolyl-4-Hydroxylase-2, Stabilizes HIF-1α Expression, and Normalizes Immature Vasculature in db/db Mice

Chen

Stinnett

2008

Diabetes

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OBJECTIVE— Diabetic impaired angiogenesis is associated with impairment of hypoxia-inducible factor-1α (HIF-1α) as well as vasculature maturation. We investigated the potential roles and intracellular mechanisms of angiopoietin-1 (Ang-1) gene therapy on myocardial HIF-1α stabilization and vascular maturation in db/db mice. RESEARCH DESIGN AND METHODS— db/db mice were systemically administrated adenovirus Ang-1 (Ad-CMV-Ang-1). Myocardial HIF-1α, vascular endothelial growth factor (VEGF), hemeoxygenase-1 (HO-1), endothelial nitric oxide synthase (eNOS), Akt, and HIF-1α–prolyl-4-hydroxylase-2 (PHD)2 expression were measured. Vasculature maturation, capillary and arteriole densities, and cardiac interstitial fibrosis were analyzed in the border zone of infarcted myocardium. RESULTS— Systemic administration of Ad-CMV-Ang-1 results in overexpression of Ang-1 in db/db mice hearts. Ang-1 gene therapy causes a significant increase in Akt and eNOS expression and HIF-1α stabilization. This is accompanied by a significant upregulation of VEGF and HO-1 expression. Intriguingly, Ang-1 gene therapy also leads to a significant inhibition of PHD2 expression. Smooth muscle recruitment and smooth muscle coverage in the neovessels of the border zone of infarcted myocardium are severely impaired in db/db mice compared with wild-type mice. Ang-1 gene therapy rescues these abnormalities, which leads to a dramatic increase in capillary and arteriole densities and a significant reduction of cardiac hypertrophy and interstitial fibrosis at 14 days after ischemia. Taken together, our data show that Ang-1 increases myocardial vascular maturation and angiogenesis together with suppression of PHD2 and the upregulation of HIF-1α signaling. CONCLUSIONS— Normalization of immature vasculature by Ang-1 gene therapy may represent a novel therapeutic strategy for treatment of the diabetes-associated impairment of myocardial angiogenesis.

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Angiopoietin-2 Causes Inflammation in Vivo by Promoting Vascular Leakage

Abstract: Angiopoietins (Angs) are endothelium-selective ligands that exert most of their actions through the Tie-2 receptor.

Cited by 208 publications

References 34 publications

Angiopoietin 2 concentrations in infants developing bronchopulmonary dysplasia: attenuation by dexamethasone

Angiopoietin 2 concentrations in infants developing bronchopulmonary dysplasia: attenuation by dexamethasone

A Neurovascular Niche for Neurogenesis after Stroke

Ang-1 Gene Therapy Inhibits Hypoxia-Inducible Factor-1α (HIF-1α)-Prolyl-4-Hydroxylase-2, Stabilizes HIF-1α Expression, and Normalizes Immature Vasculature in db/db Mice

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