Suppression of angiogenesis by lentiviral delivery of PEX, a noncatalytic fragment of matrix metalloproteinase 2

Suppression of angiogenesis by lentiviral delivery of PEX, a noncatalytic fragment of matrix metalloproteinase 2

^*The Salk Institute, La Jolla, CA 92037; and ^‡The Scripps Research Institute, La Jolla, CA 92037

Contributed by Inder M. Verma

Abstract

Modulation of the balance between pro- and antiangiogenic factors holds great promise for the treatment of a broad spectrum of human disease ranging from ischemic heart disease to cancer. This requires both the identification of angiogenic regulators and their efficient delivery to target organs. Here, we demonstrate the use of a noncatalytic fragment of matrix metalloproteinase 2 (termed PEX) delivered by lentiviral vectors in different angiogenesis models. Transduction of human endothelial cells with PEX virus suppressed endothelial invasion and formation of capillary-like structures without affecting chemotaxis in vitro. Lentiviral delivery of PEX blocked basic fibroblast growth factor-induced matrix metalloproteinase 2 activation and angiogenesis on chicken chorioallantoic membranes. PEX expression also inhibited tumor-induced angiogenesis and tumor growth in a nude mouse model. Thus, our study shows that lentiviral vectors can deliver sufficient quantities of antiangiogenic substances to achieve therapeutic effects in vivo.

Footnotes

↵ † A.P. and T.K. contributed equally to this work.
↵ § Present address: University of California San Diego, La Jolla, CA 92037.
↵ ¶ To whom reprint requests should be addressed at: Laboratory of Genetics, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037. E-mail: verma{at}salk.edu.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.220399597.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.220399597
Abbreviations:

CAM,

chicken chorioallantoic membrane;

MMP,

matrix metalloproteinase;

HUVECs,

human umbilical vein endothelial cells;

LTR,

long terminal repeat;

PEX,

hemopexin domain of MMP-2;

MT1-MMP,

membrane type 1 MMP;

SIN,

self-inactivating;

TIMP-2,

tissue inhibitor of metalloproteinase 2;

bFGF,

basic fibroblast growth factor;

I.U.,

infectious units;

GFP,

green fluorescent protein;

VSV-G,

G protein of vesicular stomatitis virus