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Blood, 15 January 2006, Vol. 107, No. 2, pp. 550-557.
Prepublished online as a Blood First Edition Paper on September 27, 2005; DOI 10.1182/blood-2005-05-2047.
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Submitted May 27, 2005
Accepted September 6, 2005
Redundant roles of VEGF-B and PlGF during selective VEGF-A blockade in mice
Ajay K Malik, Megan E Baldwin, Frank Peale, Germaine Fuh, Wei-Chin Liang, Henry Lowman, Gloria Meng, Napoleone Ferrara, and Hans-Peter Gerber*
Departments of Pathology, Protein Engineering, Antibody Engineering, Assay and Automation Technology, and Molecular Oncology, Genentech, Inc, South San Francisco, CA, USA
* Corresponding author; email: gerberhp{at}gene.com.
Vascular endothelial growth factor-A (VEGF-A) and its two transmembrane tyrosine-kinase receptors, VEGFR-1 and VEGFR-2, constitute a ligand-receptor signaling system that is crucial for developmental angiogenesis. VEGF-B and placental growth factor (PIGF) activate VEGFR-1 selectively, however, mice lacking either ligand display only minor developmental defects. We hypothesized that the relative contributions of VEGF-B and PlGF to VEGFR-1 signaling may be masked in presence of VEGF-A, which is abundantly expressed during postnatal development. To test this hypothesis, neonatal or adult mice were treated with a monoclonal antibody (G6-23-IgG) blocking murine VEGF-A or a soluble VEGFR-1 receptor IgG chimeric construct [mFlt(1-3)-IgG], that neutralizes VEGF-A, VEGF-B, and PlGF. Both compounds attenuated growth and survival of neonatal mice to similar extents and the pathophysiologic alterations, including a reduction in organ size and vascularization, changes in gene-expression and hematological endpoints were essentially indistinguishable. In adult mice, we observed only minor changes in response to treatment, which were similar between both anti-VEGF compounds. In conclusion, our findings suggest that PlGF and VEGF-B do not compensate during conditions of VEGF-A blockade, suggesting a minor role for compensatory VEGFR-1 signaling during postnatal development and vascular homeostasis in adults. The absence of compensatory VEGFR-1 signaling by VEGF-B and PlGF may have important implications for the development of anticancer strategies targeting the VEGF ligand/receptor system.
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