Medline ® Abstract for Reference 32
of 'Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects'
VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis.
Tam BY, Wei K, Rudge JS, Hoffman J, Holash J, Park SK, Yuan J, Hefner C, Chartier C, Lee JS, Jiang S, Nayak NR, Kuypers FA, Ma L, Sundram U, Wu G, Garcia JA, Schrier SL, Maher JJ, Johnson RS, Yancopoulos GD, Mulligan RC, Kuo CJ
Nat Med. 2006;12(7):793. Epub 2006 Jun 25.
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-1alpha-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 ofEpo and erythrocytosis could represent noninvasive surrogate markers for stringent blockade of VEGF in vivo.
Division of Hematology, Stanford University School of Medicine, 269 Campus Drive, CCSR 1155, Stanford, California, 94305, USA.