Nature Medicine
- 12, 793 - 800 (2006)
Published online: 25 June 2006; Corrected online: 06 April 2009 | doi:10.1038/nm1428
There is a Corrigendum (April 2009) associated with this Article.
VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesisBetty Y Y Tam1, 10, 11, Kevin Wei1, 11, John S Rudge2, Jana Hoffman1, Joceyln Holash2, Sang-ki Park3, 10, Jenny Yuan1, Colleen Hefner4, Cecile Chartier1, Jeng-Shin Lee5, Shelly Jiang2, Nihar R Nayak6, Frans A Kuypers7, Lisa Ma1, Uma Sundram8, Grace Wu1, Joseph A Garcia9, Stanley L Schrier1, Jacquelyn J Maher4, Randall S Johnson3, George D Yancopoulos2, Richard C Mulligan5 & Calvin J Kuo11
Division of Hematology, Stanford University School of Medicine, 269 Campus Drive, CCSR 1155, Stanford, California, 94305, USA. 2
Regeneron Pharmaceuticals, Incorporated, 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA. 3
University of California, San Diego, Molecular Biology Section, Division of Biological Sciences, 9500 Gilman Drive, La Jolla, California 92093, USA. 4
Liver Center and Department of Medicine, S-357 University of California, San Francisco, California 94143, USA. 5
Department of Genetics, Harvard Medical School, Division of Molecular Medicine, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA. 6
Division of Gynecology and Obstetrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA. 7
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, California 94609, USA. 8
Division of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA. 9
University of Texas Southwestern Medical Center at Dallas, Division of Cardiology MC8573, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA. 10
Present addresses: TargeGen Inc., 9380 Judicial Drive, San Diego, California 92121, USA (B.Y.Y.T.) and Department of Pharmaceutical Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York 11438, USA (S.-K.P.). 11
These authors contributed equally to this work.
Correspondence should be addressed to Calvin J Kuo cjkuo@stanford.edu Vascular endothelial growth factor (VEGF) exerts crucial functions during pathological angiogenesis and normal physiology. We observed increased hematocrit (60–75%) after high-grade inhibition of VEGF by diverse methods, including adenoviral expression of soluble VEGF receptor (VEGFR) ectodomains, recombinant VEGF Trap protein and the VEGFR2-selective antibody DC101. Increased production of red blood cells (erythrocytosis) occurred in both mouse and primate models, and was associated with near-complete neutralization of VEGF corneal micropocket angiogenesis. High-grade inhibition of VEGF induced hepatic synthesis of erythropoietin (Epo, encoded by Epo) >40-fold through a HIF-1 –independent mechanism, in parallel with suppression of renal Epo mRNA. Studies using hepatocyte-specific deletion of the Vegfa gene and hepatocyte–endothelial cell cocultures indicated that blockade of VEGF induced hepatic Epo by interfering with homeostatic VEGFR2-dependent paracrine signaling involving interactions between hepatocytes and endothelial cells. These data indicate that VEGF is a previously unsuspected negative regulator of hepatic Epo synthesis and erythropoiesis and suggest that levels of Epo and erythrocytosis could represent noninvasive surrogate markers for stringent blockade of VEGF in vivo.
NOTE: In the version of this article initially published, the name of one of the authors, Nihar R. Nayak, was misspelled as Nihar R. Niyak. The error has been corrected in the HTML and PDF versions of the article.
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