Angiopoietin-2 Is Required for Postnatal Angiogenesis and Lymphatic Patterning, and Only the Latter Role Is Rescued by Angiopoietin-1

Gale, Nicholas W.; Thurston, Gavin; Hackett, Sean F.; Renard, R.A.; Wang, Quan; McClain, Joyce; Martin, C.; Witte, Charles L.; Witte, Marlys H.; Jackson, David G.; Suri, Chitra; Campochiaro, Peter A.; Wiegand, Stanley J.; Yancopouloš, George D.

doi:10.1016/s1534-5807(02)00217-4

Cited by 905 publications

(898 citation statements)

References 32 publications

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“…22 Ang2 is also required for normal lymphatic vessel formation. 23 Mouse Ang3 and human Ang4 are interspecies orthologues, 18 whose functions have not yet been clarified. The function of Tie1 is less well characterized than that of Tie2 because of the lack of its own specific ligands, although it has been recently shown that the Tie1 receptor can interact with Tie2 and signal as a heterodimeric complex.…”

Section: Introductionmentioning

confidence: 99%

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

et al. 2010

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Despite optimal surgery and chemotherapy, the prognosis of ovarian cancer patients remains poor and new treatments are urgently needed. Solid tumors require the formation of new vessels for growth and metastasis. In the present study, we have used soluble vascular endothelial growth factor (sVEGF) receptors sVEGFR-1 and -3, soluble receptors Tie1 and Tie2 and their combinations in an ovarian cancer xenograft model. Human ovarian cancer cells were injected intraperitoneally into nude mice (n ¼ 42) and magnetic resonance imaging (MRI) was used for confirming tumors before gene delivery. Treatment with combined AdsVEGFR-1, AdsVEGFR-3 and AdsTie2 significantly decreased the size of the intraperitoneal tumors compared with the controls (AdLacZ; P ¼ 0.038) with significantly less microvessels and vascular area. Unexpectedly, treatment with combined AdsTie1 and AdsTie2 led to a dramatic shortening of the survival which was not observed in the groups receiving either of the soluble receptors alone (P ¼ 0.031). The only difference to other treatments was liver toxicity observed after the combined Tie receptor treatment.In conclusion, combined inhibition of VEGFR-1, VEGFR-3 and Tie2 pathways was safe and provided efficient therapy for ovarian cancer in mice.

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Section: Introductionmentioning

confidence: 99%

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

et al. 2010

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“…2 Inflammation interferes with the normal development of airways and alveoli, and abnormal healing in the premature infant further exacerbates lung damage, resulting in BPD. 2 While the role of angiopoietin 2 (Ang2) in regulating angiogenesis and vascular integrity has been well recognized, 7,8 recent reports have implicated an important role in inflammation. [9][10][11][12] Ang2 expression is increased dramatically at the sites of endothelial activation and is induced by various cytokines.…”

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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“…Ang2 is predominantly expressed by smooth muscle cells of large arteries, large veins, and venules, and its expression by endothelial cells is activated by VEGF-A and hypoxia, in particular at sites of vascular remodeling (Mandriota and Pepper, 1998;Holash et al, 1999a,b;Mandriota et al, 2000). A recent study of Ang2 knockout mice surprisingly also revealed abnormalities of the lymphatic system (Gale et al, 2002). Whereas Ang-2 was not required for embryonic vasculogenesis, it was necessary for postnatal angiogenesis and vessel regression in the eye.…”

Section: Angiopoietin-2mentioning

confidence: 99%

“…Ang2 was not required for the early formation of lymphatic vessels, but the large lymphatic vessels of Ang2 mutant mice were structurally irregular and leaky, and the smaller lymphatic vessels displayed abnormal patterning. Strikingly, the defects of the lymphatic but not of the blood vascular system in Ang2-deficient mice could be functionally rescued by overexpression of Ang1, adding additional complexity to the relative functions of Ang1 and Ang2 and their potential interplay with other angiogenic factors (Gale et al, 2002).…”

Section: Angiopoietin-2mentioning

confidence: 99%

Development of the lymphatic vascular system: A mystery unravels

Hong

Shin

Detmar

2004

Developmental Dynamics

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The blood vascular and the lymphatic system play complementary roles in tissue perfusion and fluid reabsorption. Despite its critical role in mediating tissue fluid homeostasis, intestinal lipid absorption, and the immune response, the lymphatic system has not received as much attention as the blood vascular system, largely due to a lack of lymphatic-specific markers and to the dearth of knowledge about the molecular regulation of lymphatic development and function. A series of recent landmark studies now significantly has advanced our understanding of the lymphatic system. Based upon the discovery and characterization of lymphatic-specific growth factors, receptors, and transcriptional regulators, the mystery of lymphatic vascular system development begins to be unraveled. The successful isolation and cultivation of blood vascular and lymphatic endothelial cells has enabled comparative molecular and cellular analyses of these two genetically and developmentally closely related cell lineages. Moreover, studies of several genetic mouse models have set the framework for a new molecular model of embryonic lymphatic vascular development and have identified molecular pathways whose mutational inactivation leads to human diseases associated with lymphedema. Although these rapid advances already have led to development of the first lymphatic-targeted molecular therapies, there still remain many unanswered questions regarding almost every aspect of lymphatic vascular biology, making the lymphatic system a highly exciting and rewarding field of study.

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Angiopoietin-2 Is Required for Postnatal Angiogenesis and Lymphatic Patterning, and Only the Latter Role Is Rescued by Angiopoietin-1

Cited by 905 publications

References 32 publications

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

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

Development of the lymphatic vascular system: A mystery unravels

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