Angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules

Baffert, Fabienne; Le, Tom; Thurston, Gavin; McDonald, Donald M.

doi:10.1152/ajpheart.00542.2005

Cited by 129 publications

(113 citation statements)

References 47 publications

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“…In vivo experiments showed that vessel maturation in response to IFN-h could be impaired by interfering with angiopoietin signaling using a soluble, truncated Tie2 receptor, further supporting a central role for angiopoietin-1 in the process of vascular normalization effected by IFN-h. These findings are consistent with previous studies that have suggested a role for angiopoietin-1 in vessel stabilization (27) and decreased vessel permeability (35) and reveal a novel method for effecting angiopoietin-1 upregulation through continuous delivery of IFN-h. Although Tie2 blockade seemed to completely reverse perivascular cell recruitment to tumor vessels, this only partially abrogated the improvement in intratumoral drug delivery, suggesting that other factors, in addition to perivascular cell coverage of tumor vessels, may contribute to the functional improvement of these vessels in response to continuous IFN-h delivery.…”

Section: Discussionsupporting

confidence: 93%

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Dickson¹,

Hamner²,

Streck³

et al. 2007

Molecular Cancer Research

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IFNs have pleiotropic antitumor mechanisms of action. The purpose of this study was to further investigate the effects of IFN-B on the vasculature of human xenografts in immunodeficient mice. We found that continuous, systemic IFN-B delivery, established with liver-targeted adeno-associated virus vectors, led to sustained morphologic and functional changes of the tumor vasculature that were consistent with vessel maturation. These changes included increased smooth muscle cell coverage of tumor vessels, improved intratumoral blood flow, and decreased vessel permeability, tumor interstitial pressure, and intratumoral hypoxia. Although these changes in the tumor vasculature resulted in more efficient tumor perfusion, further tumor growth was restricted, as the mature vasculature seemed to be unable to expand to support further tumor growth. In addition, maturation of the intratumoral vasculature resulted in increased intratumoral penetration of systemically administered chemotherapy. Finally, molecular analysis revealed increased expression by treated tumors of angiopoietin-1, a cytokine known to promote vessel stabilization. Induction of angiopoietin-1 expression in response to IFN-B was broadly observed in different tumor lines but not in those with defects in IFN signaling. In addition, IFN-B -mediated vascular changes were prevented when angiopoietin signaling was blocked with a decoy receptor. Thus, we have identified an alternative approach for achieving sustained vascular remodeling-continuous delivery of IFN-B. In addition to restricting tumor growth by inhibiting further angiogenesis, maturation of the tumor vasculature also improved the efficiency of delivery of adjuvant therapy. These results have significant implications for the planning of combination anticancer therapy.

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Section: Discussionsupporting

confidence: 93%

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Dickson¹,

Hamner²,

Streck³

et al. 2007

Molecular Cancer Research

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“…In addition, these remodeled blood vessels have abnormalities in endothelial barrier function and are leaky. The role of the angiopoietin family members has been demonstrated in the vascular remodeling process occurring in asthma and chronic bronchitis [20,21]. Similarly, we found that CF epithelial cells express more Ang1 and angiopoietin like-2 than control epithelial cells.…”

Section: Discussionsupporting

confidence: 80%

Intrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells

Verhaeghe

Tabruyn

Oury

2007

Biochemical and Biophysical Research Communications

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Cystic fibrosis is a common genetic disorder characterized by a severe lung inflammation and fibrosis leading to the patient's death. Enhanced angiogenesis in cystic fibrosis (CF) tissue has been suggested, probably caused by the process of inflammation, as similarly described in asthma and chronic bronchitis. The present study demonstrates an intrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells. Microarray experiments showed that CF airway epithelial cells expressed several angiogenic factors such as VEGF-A, VEGF-C, bFGF, and PLGF at higher levels than control cells. These data were confirmed by real-time quantitative PCR and, at the protein level, by ELISA. Conditioned media of these cystic fibrosis cells were able to induce proliferation, migration and sprouting of cultured primary endothelial cells. This report describes for the first time that cystic fibrosis epithelial cells have an intrinsic angiogenic activity. Since excess of angiogenesis is correlated with more severe pulmonary disease, our results could lead to the development of new therapeutic applications.

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“…(B -D) Confocal microscopic images of tracheal capillaries showing deposits of fibrin in nonpatent segment of tracheal capillary after inhibition of VEGF signalling by AG-013736 for 1 day. Fibrin deposit (arrow) is shown to be in a nonperfused capillary segment by absence of lectin binding, and is near a region of capillary regression that lacks CD31 immunoreactivity (arrowheads) (Baffert et al, 2006b). (E -F) Confocal images of tracheal vasculature showing apoptotic endothelial cells stained for activated caspase-3 (arrow), near region of capillary regression (arrowheads) shown by absence of CD31 immunoreactivity (E).…”

Section: Assessment Of Adverse Effects Of Vegf Signalling Inhibitors mentioning

confidence: 99%

Mechanisms of adverse effects of anti-VEGF therapy for cancer

2007

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Advances in understanding the role of vascular endothelial growth factor (VEGF) in normal physiology are giving insight into the basis of adverse effects attributed to the use of VEGF inhibitors in clinical oncology. These effects are typically downstream consequences of suppression of cellular signalling pathways important in the regulation and maintenance of the microvasculature. Downregulation of these pathways in normal organs can lead to vascular disturbances and even regression of blood vessels, which could be intensified by concurrent pathological conditions. These changes are generally manageable and pose less risk than the tumours being treated, but they highlight the properties shared by tumour vessels and the vasculature of normal organs.

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Angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules

Abstract: decreases plasma leakage by reducing number and size of endothelial gaps in venules.

Cited by 129 publications

References 47 publications

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Intrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells

Mechanisms of adverse effects of anti-VEGF therapy for cancer

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