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

Abstract

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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Figure 1: Therapeutic angiogenesis and arteriogenesis with PlGF in the ischemic myocardium and limb.
Figure 2: PlGF stimulates, whereas anti-Flt1 inhibits vessel growth.
Figure 3: Anti-Flt1 mAb inhibits inflammation but not angiogenesis in atherosclerotic plaques.
Figure 4: Anti-Flt1, but not anti-Flk1, inhibits arthritic joint destruction.

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Acknowledgements

We thank A. Bouché, K. Vandevelde, Y. Wing Man, I. Vanlinthout, M. De Mol, K. Maris, B. Vanwetswinkel, A. Manderveld, B. Hermans, P. Van Wesemael, S. Jansen, W. Martens, A. Vandenhoeck, S. Terclavers, S. Wyns, W. Landuyt and S. Torrekens for assistance. This work was supported in part by the European Union (Biomed BMH4-CT98-3380), Actie Levenslijn (#7.0019.98), FWO (G012500 and G032401) and a KUL/OT grant (TBA/00/27). A.L. and V.C. are FWO research fellows. M.T. is an IWT research fellow.

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Correspondence to Peter Carmeliet.

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The anti-Flt1 monoclonal antibody was generated by ImClone Systems Inc. Y.W., F.L., A.H., P.B. and D. Hicklin are employed by ImClone. D.C. is employed by ThrombX; the center for Transgene Technology as received support from ThrombX for the research program evaluating the therapeutic potential of PlGF for heart and limb ischemia.

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Luttun, A., Tjwa, M., Moons, L. et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8, 831–840 (2002). https://doi.org/10.1038/nm731

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