Inhibition of angiogenesis in vitro by αv integrin-directed antisense oligonucleotides

Ralf Kronenwett, Thorsten Gräf, Wolfgang Nedbal, Markus Weber, Ulrich G. Steidl, Ulrich Peter Rohr, Thomas Möhler, Rainer Haas

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The integrin αvβ3 plays a central role in angiogenesis. In this study, we used antisense oligodeoxyribonucleotides (ONs) directed against the αv subunit of αvβ3 to inhibit integrin expression. Ten ON sequences, which were selected by systematic alignment of computer-predicted secondary structures of αv mRNA, were transfected into human umbilical vein endothelial cells (HUVECs). Following stimulation by PMA, five antisense ONs significantly inhibited αv mRNA and protein expression in activated HUVEC at a concentration of 0.05 μM with complete prevention of PMA-induced αv up-regulation by the most potent antisense ON. Inhibition of αv expression was associated with significant inhibition of migration of HUVEC by 28% and had no effect on proliferation and apoptosis. Moreover, transfection of antisense ON inhibited the formation of tube-like structures of HUVEC in Matrigel by 44%. In a cell culture model of angiogenesis consisting of a co-culture of endothelial cells with fibroblasts, transfection of antisense ONs resulted in an inhibition of tube formation of 61%. In conclusion, αv antisense ONs are potent inhibitors of angiogenesis in vitro. They might, therefore, be a therapeutic alternative to antagonists, which directly bind to αv integrins, and might be useful for the treatment of malignant tumors and hematological malignancies.

Original languageEnglish (US)
Pages (from-to)587-596
Number of pages10
JournalCancer Gene Therapy
Volume9
Issue number7
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Antisense Oligodeoxyribonucleotides
Antisense Oligonucleotides
Integrins
Human Umbilical Vein Endothelial Cells
Transfection
Messenger RNA
Angiogenesis Inhibitors
Oligodeoxyribonucleotides
Hematologic Neoplasms
Coculture Techniques
In Vitro Techniques
Up-Regulation
Endothelial Cells
Cell Culture Techniques
Fibroblasts
Apoptosis

Keywords

  • Alpha V integrin
  • Angiogenesis
  • Antagonist
  • Antisense oligonucleotides

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Inhibition of angiogenesis in vitro by αv integrin-directed antisense oligonucleotides. / Kronenwett, Ralf; Gräf, Thorsten; Nedbal, Wolfgang; Weber, Markus; Steidl, Ulrich G.; Rohr, Ulrich Peter; Möhler, Thomas; Haas, Rainer.

In: Cancer Gene Therapy, Vol. 9, No. 7, 2002, p. 587-596.

Research output: Contribution to journalArticle

Kronenwett, R, Gräf, T, Nedbal, W, Weber, M, Steidl, UG, Rohr, UP, Möhler, T & Haas, R 2002, 'Inhibition of angiogenesis in vitro by αv integrin-directed antisense oligonucleotides', Cancer Gene Therapy, vol. 9, no. 7, pp. 587-596. https://doi.org/10.1038/sj.cgt.7700474
Kronenwett, Ralf ; Gräf, Thorsten ; Nedbal, Wolfgang ; Weber, Markus ; Steidl, Ulrich G. ; Rohr, Ulrich Peter ; Möhler, Thomas ; Haas, Rainer. / Inhibition of angiogenesis in vitro by αv integrin-directed antisense oligonucleotides. In: Cancer Gene Therapy. 2002 ; Vol. 9, No. 7. pp. 587-596.
@article{d7017653d35d47ff9e01ebf440628297,
title = "Inhibition of angiogenesis in vitro by αv integrin-directed antisense oligonucleotides",
abstract = "The integrin αvβ3 plays a central role in angiogenesis. In this study, we used antisense oligodeoxyribonucleotides (ONs) directed against the αv subunit of αvβ3 to inhibit integrin expression. Ten ON sequences, which were selected by systematic alignment of computer-predicted secondary structures of αv mRNA, were transfected into human umbilical vein endothelial cells (HUVECs). Following stimulation by PMA, five antisense ONs significantly inhibited αv mRNA and protein expression in activated HUVEC at a concentration of 0.05 μM with complete prevention of PMA-induced αv up-regulation by the most potent antisense ON. Inhibition of αv expression was associated with significant inhibition of migration of HUVEC by 28{\%} and had no effect on proliferation and apoptosis. Moreover, transfection of antisense ON inhibited the formation of tube-like structures of HUVEC in Matrigel by 44{\%}. In a cell culture model of angiogenesis consisting of a co-culture of endothelial cells with fibroblasts, transfection of antisense ONs resulted in an inhibition of tube formation of 61{\%}. In conclusion, αv antisense ONs are potent inhibitors of angiogenesis in vitro. They might, therefore, be a therapeutic alternative to antagonists, which directly bind to αv integrins, and might be useful for the treatment of malignant tumors and hematological malignancies.",
keywords = "Alpha V integrin, Angiogenesis, Antagonist, Antisense oligonucleotides",
author = "Ralf Kronenwett and Thorsten Gr{\"a}f and Wolfgang Nedbal and Markus Weber and Steidl, {Ulrich G.} and Rohr, {Ulrich Peter} and Thomas M{\"o}hler and Rainer Haas",
year = "2002",
doi = "10.1038/sj.cgt.7700474",
language = "English (US)",
volume = "9",
pages = "587--596",
journal = "Cancer Gene Therapy",
issn = "0929-1903",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Inhibition of angiogenesis in vitro by αv integrin-directed antisense oligonucleotides

AU - Kronenwett, Ralf

AU - Gräf, Thorsten

AU - Nedbal, Wolfgang

AU - Weber, Markus

AU - Steidl, Ulrich G.

AU - Rohr, Ulrich Peter

AU - Möhler, Thomas

AU - Haas, Rainer

PY - 2002

Y1 - 2002

N2 - The integrin αvβ3 plays a central role in angiogenesis. In this study, we used antisense oligodeoxyribonucleotides (ONs) directed against the αv subunit of αvβ3 to inhibit integrin expression. Ten ON sequences, which were selected by systematic alignment of computer-predicted secondary structures of αv mRNA, were transfected into human umbilical vein endothelial cells (HUVECs). Following stimulation by PMA, five antisense ONs significantly inhibited αv mRNA and protein expression in activated HUVEC at a concentration of 0.05 μM with complete prevention of PMA-induced αv up-regulation by the most potent antisense ON. Inhibition of αv expression was associated with significant inhibition of migration of HUVEC by 28% and had no effect on proliferation and apoptosis. Moreover, transfection of antisense ON inhibited the formation of tube-like structures of HUVEC in Matrigel by 44%. In a cell culture model of angiogenesis consisting of a co-culture of endothelial cells with fibroblasts, transfection of antisense ONs resulted in an inhibition of tube formation of 61%. In conclusion, αv antisense ONs are potent inhibitors of angiogenesis in vitro. They might, therefore, be a therapeutic alternative to antagonists, which directly bind to αv integrins, and might be useful for the treatment of malignant tumors and hematological malignancies.

AB - The integrin αvβ3 plays a central role in angiogenesis. In this study, we used antisense oligodeoxyribonucleotides (ONs) directed against the αv subunit of αvβ3 to inhibit integrin expression. Ten ON sequences, which were selected by systematic alignment of computer-predicted secondary structures of αv mRNA, were transfected into human umbilical vein endothelial cells (HUVECs). Following stimulation by PMA, five antisense ONs significantly inhibited αv mRNA and protein expression in activated HUVEC at a concentration of 0.05 μM with complete prevention of PMA-induced αv up-regulation by the most potent antisense ON. Inhibition of αv expression was associated with significant inhibition of migration of HUVEC by 28% and had no effect on proliferation and apoptosis. Moreover, transfection of antisense ON inhibited the formation of tube-like structures of HUVEC in Matrigel by 44%. In a cell culture model of angiogenesis consisting of a co-culture of endothelial cells with fibroblasts, transfection of antisense ONs resulted in an inhibition of tube formation of 61%. In conclusion, αv antisense ONs are potent inhibitors of angiogenesis in vitro. They might, therefore, be a therapeutic alternative to antagonists, which directly bind to αv integrins, and might be useful for the treatment of malignant tumors and hematological malignancies.

KW - Alpha V integrin

KW - Angiogenesis

KW - Antagonist

KW - Antisense oligonucleotides

UR - http://www.scopus.com/inward/record.url?scp=0036019375&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036019375&partnerID=8YFLogxK

U2 - 10.1038/sj.cgt.7700474

DO - 10.1038/sj.cgt.7700474

M3 - Article

VL - 9

SP - 587

EP - 596

JO - Cancer Gene Therapy

JF - Cancer Gene Therapy

SN - 0929-1903

IS - 7

ER -