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Article
Nature Medicine  8, 831 - 840 (2002)
Published online: 1 July 2002; | doi:10.1038/nm731

Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1

Aernout Luttun1, 10, Marc Tjwa1, 10, Lieve Moons1, Yan Wu4, Anne Angelillo-Scherrer5, Fang Liao4, Janice A. Nagy6, Andrea Hooper4, Josef Priller7, Bert De Klerck2, Veerle Compernolle1, Evis Daci3, Peter Bohlen4, Mieke Dewerchin1, Jean-Marc Herbert8, Roy Fava9, Patrick Matthys2, Geert Carmeliet3, Désiré Collen1, Harold F. Dvorak6, Daniel J. Hicklin4 & Peter Carmeliet1

1  Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology; University of Leuven, Leuven, Belgium

2  Laboratory of Immunobiology, Rega Institute for Medical Research; University of Leuven, Leuven, Belgium

3  Laboratory of Experimental Medicine and Endocrinology, University of Leuven, Leuven, Belgium

4  ImClone Systems Inc., New York, New York, USA

5  Division of Angiology and Hemostasis, University Medical Center, Geneva, Switzerland

6  Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

7  Department of Neurology, Charité, Humboldt-University, Berlin, Germany

8  Cardiovascular/Thrombosis Research Department, Sanofi-Synthélabo, Toulouse Cedex, France

9  Department of Veterans Affairs Medical Center, White River Junction, Vermont and Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire, USA

10  A.L. and M.T. contributed equally to this study.

Correspondence should be addressed to Peter Carmeliet peter.carmeliet@med.kuleuven.ac.be
The therapeutic potential of placental growth factor (PlGF) and its receptor Flt1 in angiogenesis is poorly understood. Here, we report that PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to vascular endothelial growth factor (VEGF). An antibody against Flt1 suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. Anti-Flt1 also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not attributable to reduced plaque neovascularization. Inhibition of VEGF receptor Flk1 did not affect arthritis or atherosclerosis, indicating that inhibition of Flk1-driven angiogenesis alone was not sufficient to halt disease progression. The anti-inflammatory effects of anti-Flt1 were attributable to reduced mobilization of bone marrow−derived myeloid progenitors into the peripheral blood; impaired infiltration of Flt1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells. Thus, PlGF and Flt1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.

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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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