The Notch signalling pathway is a key regulator of developmental and tumour angiogenesis. Inhibition of Delta-like 4 (Dll4)-mediated Notch signalling results in hyper-sprouting, demonstrating that Notch regulates tip-stalk cell identity in developing tissues and tumours. Paradoxically, Dll4 blockade leads to reduced tumour growth because the newly growing vessels are poorly perfused. To explore the potential for targeting Notch, we developed Notch inhibitors, termed the Notch1 decoys. A Notch1 decoy variant containing all 36 epidermal growth factor (EGF)-like repeats of the extracellular domain of rat Notch1 has been shown to inhibit both Dll and Jagged class Notch ligands. Thus this Notch1 decoy functions differently than Dll4-specific blockade, although it has the potential to inhibit Dll4 activity. Expression of the Notch1 decoy in mice disrupted tumour angiogenesis and inhibited tumour growth. To understand the mechanism by which Notch blockade acts, it is important to note that Notch can function in multiple cell types that make up the vasculature, including endothelial cells and perivascular cells. We investigated Notch function in retinal microglia and determined how myeloid-expressed Notch can influence macrophages and angiogenesis. We found that myeloid-specific loss of Notch1 reduced microglia recruitment and led to improper microglia localization during retinal angiogenesis. Thus either pharmacological inhibition of Notch signalling or genetic deficiencies of Notch function in microglia leads to abnormal angiogenesis.
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December 2014
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Conference Article|
November 17 2014
Notch functions in developmental and tumour angiogenesis by diverse mechanisms1
Thaned Kangsamaksin;
Thaned Kangsamaksin
*Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
†Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, U.S.A.
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Ian W. Tattersall;
Ian W. Tattersall
†Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, U.S.A.
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Jan Kitajewski
Jan Kitajewski
2
†Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, U.S.A.
‡Department of Pathology, Columbia University Medical Center, New York, NY 10032, U.S.A.
§Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, U.S.A.
2To whom correspondence should be addressed (emailjkk9@columbia.edu).
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Publisher: Portland Press Ltd
Received:
August 26 2014
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem Soc Trans (2014) 42 (6): 1563–1568.
Article history
Received:
August 26 2014
Citation
Thaned Kangsamaksin, Ian W. Tattersall, Jan Kitajewski; Notch functions in developmental and tumour angiogenesis by diverse mechanisms1. Biochem Soc Trans 1 December 2014; 42 (6): 1563–1568. doi: https://doi.org/10.1042/BST20140233
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