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Human α1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by α1β1 integrin
Akulapalli Sudhakar, … , Dominic Cosgrove, Raghu Kalluri
Akulapalli Sudhakar, … , Dominic Cosgrove, Raghu Kalluri
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2801-2810. https://doi.org/10.1172/JCI24813.
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Research Article Angiogenesis

Human α1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by α1β1 integrin

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Abstract

Human noncollagenous domain 1 of the α1 chain of type IV collagen [α1(IV)NC1], or arresten, is derived from the carboxy terminal of type IV collagen. It was shown to inhibit angiogenesis and tumor growth in vivo; however, the mechanisms involved are not known. In the present study we demonstrate that human α1(IV)NC1 binds to α1β1 integrin, competes with type IV collagen binding to α1β1 integrin, and inhibits migration, proliferation, and tube formation by ECs. Also, α1(IV)NC1 pretreatment inhibited FAK/c-Raf/MEK/ERK1/2/p38 MAPK activation in ECs but had no effect on the PI3K/Akt pathway. In contrast, α1(IV)NC1 did not affect proliferation, migration, or the activation of FAK/c-Raf/MEK1/2/p38/ERK1 MAPK pathway in α1 integrin receptor knockout ECs. Consistent with this, α1(IV)NC1 elicited significant antiangiogenic effects and tumor growth inhibition in vivo but failed to do the same in α1 integrin receptor knockout mice. This suggests a highly specific, α1β1 integrin–dependent antiangiogenic activity of α1(IV)NC1. In addition, α1(IV)NC1 inhibited hypoxia-induced expression of hypoxia-inducible factor 1α and VEGF in ECs cultured on type IV collagen by inhibiting ERK1/2 and p38 activation. This unravels a hitherto unknown function of human α1(IV)NC1 and suggests a critical role for integrins in hypoxia and hypoxia-induced angiogenesis. Collectively, the above data indicate that α1(IV)NC1 is a potential therapeutic candidate for targeting tumor angiogenesis.

Authors

Akulapalli Sudhakar, Pia Nyberg, Venkateshwar G. Keshamouni, Arjuna P. Mannam, Jian Li, Hikaru Sugimoto, Dominic Cosgrove, Raghu Kalluri

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Figure 1

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In vitro antiangiogenic activities of α1(IV)NC1. (A) Migration assays. N...
In vitro antiangiogenic activities of α1(IV)NC1. (A) Migration assays. Number of HUVECs migrated (arrowheads) in endothelial growth medium (EGM), EGM with α1(IV)NC1, EGM with VEGF, or EGM with VEGF and α1(IV)NC1, using a light microscope and representative fields (×100 magnification), is shown. Photographs of the underside of Boyden chamber membrane HUVECs are shown. (B) Migrated HUVECs. The graph displays the average number of cells migrated in 3 independent experiments (86.7% inhibition at 1 μM). (C) Proliferation assays. The graph summarizes the relative [3H]thymidine incorporation inhibition in HUVECs upon treatment with different concentrations of α1(IV)NC1 compared with the 10% FCS control in 3 independent experiments. (D) Tube formation assay. HUVECs were plated on Matrigel-coated plates in media control, α1(IV)NC1, soluble α1β1 protein, or both α1(IV)NC1 and soluble α1β1 protein. Tube formation was evaluated after 24 hours using a light microscope, and representative fields (×100 magnification) are shown. (E) Number of tubes. The graph displays the average percentage of tubes formed in 3 independent experiments. EBM, endothelial cell basal medium.
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