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(Circulation Research. 2004;94:1443.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Blockage of VEGF-Induced Angiogenesis by Preventing VEGF Secretion

Meit Björndahl, Renhai Cao, Anna Eriksson, Yihai Cao

From the Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden.

Correspondence to Dr. Yihai Cao, Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden. E-mail yihai.cao{at}mtc.ki.se

Vascular endothelial growth factor (VEGF)/vascular permeability factor is one of the most frequently expressed angiogenic factors in several pathological tissues. Development of VEGF antagonists has become an important approach in the treatment of angiogenesis-dependent diseases. Here we describe a novel anti-VEGF strategy by preventing the secretion of VEGF. We utilize the fact that placenta growth factor (PlGF)-1, a member of the VEGF family lacking detectable angiogenic activity, preferentially forms intracellular heterodimers with VEGF in cells coexpressing both factors. We constructed a retroviral vector containing human PlGF-1 or VEGF with a C-terminal KDEL sequence, which is a mammalian retention signal for the endoplasmic reticulum. Transduction of murine Lewis lung carcinoma cells with the retro-hPlGF-1-KDEL construct almost completely abrogated tumor growth. Consistent with the dramatic antitumor effect, most mouse VEGF molecules remained as intracellular mVEGF/hPlGF-1 heterodimers, and only a negligible amount of mVEGF homodimers were secreted. As a result, in hPlGF-1-KDEL–expressing tumors, blood vessels remained at very low numbers and lacked branching and capillary networks. Gene transfer of a hVEGF-KDEL construct into tumor cells likewise produced a dramatic antitumor effect. Thus, our study provides a novel antiangiogenic approach by preventing the secretion of VEGF.

Key Words: PlGF-1 • VEGF • angiogenesis • tumor growth • endoplasmic reticulum

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