Tissue inhibitor of metalloproteinases-3 peptides inhibit angiogenesis and choroidal neovascularization in mice

Qi, Jian Hua, Ebrahem, Quteba, Ali, Mariya, Cutler, Alecia, Bell, Brent, Prayson, Nicholas, Sears, Jonathan, Knauper, Vera ORCID: https://orcid.org/0000-0002-3965-9924, Murphy, Gillian and Anand-Apte, Bela 2013. Tissue inhibitor of metalloproteinases-3 peptides inhibit angiogenesis and choroidal neovascularization in mice. PLoS ONE 8 (3) , e55667. 10.1371/journal.pone.0055667

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Abstract

Tissue inhibitors of metalloproteinases (TIMPs) while originally characterized as inhibitors of matrix metalloproteinases (MMPs) have recently been shown to have a wide range of functions that are independent of their MMP inhibitory properties. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a potent inhibitor of VEGF-mediated angiogenesis and neovascularization through its ability to block the binding of VEGF to its receptor VEGFR-2. To identify and characterize the anti-angiogenic domain of TIMP-3, structure function analyses and synthetic peptide studies were performed using VEGF-mediated receptor binding, signaling, migration and proliferation. In addition, the ability of TIMP-3 peptides to inhibit CNV in a mouse model was evaluated. We demonstrate that the anti-angiogenic property resides in the COOH-terminal domain of TIMP-3 protein which can block the binding of VEGF specifically to its receptor VEGFR-2, but not to VEGFR-1 similar to the full-length wild-type protein. Synthetic peptides corresponding to putative loop 6 and tail region of TIMP-3 have anti-angiogenic properties as determined by inhibition of VEGF binding to VEGFR-2, VEGF-induced phosphorylation of VEGFR-2 and downstream signaling pathways as well as endothelial cell proliferation and migration in response to VEGF. In addition, we show that intravitreal administration of TIMP-3 peptide could inhibit the size of laser-induced choroidal neovascularization lesions in mice. Thus, we have identified TIMP-3 peptides to be efficient inhibitors of angiogenesis and have a potential to be used therapeutically in diseases with increased neovascularization.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Subjects:	R Medicine > RK Dentistry
Additional Information:	Pdf uploaded in accordance with the publisher’s policy at http://www.sherpa.ac.uk/romeo/issn/1932-6203/ (accessed 16/07/2014)
Publisher:	Public Library of Science
ISSN:	1932-6203
Funders:	US National Institute of Health EY016490, CA106415, EY015638, Research to Prevent Blindness (RPB) Challenge Grant, RPB Lew Wasserman award to BA-A
Date of First Compliant Deposit:	30 March 2016
Last Modified:	06 May 2023 18:07
URI:	https://orca.cardiff.ac.uk/id/eprint/61804

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