title: VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis.
abstract: 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 of Epo and erythrocytosis could represent noninvasive surrogate markers for stringent blockade of VEGF in vivo.
authors.affiliation: Division of Hematology, Stanford University School of Medicine, 269 Campus Drive, CCSR 1155, Stanford, California, 94305, USA.
authors.forename: Betty Y Y
authors.initials: BY
authors.lastname: Tam
authors.forename: Kevin
authors.initials: K
authors.lastname: Wei
authors.forename: John S
authors.initials: JS
authors.lastname: Rudge
authors.forename: Jana
authors.initials: J
authors.lastname: Hoffman
authors.forename: Joceyln
authors.initials: J
authors.lastname: Holash
authors.forename: Sang-ki
authors.initials: SK
authors.lastname: Park
authors.forename: Jenny
authors.initials: J
authors.lastname: Yuan
authors.forename: Colleen
authors.initials: C
authors.lastname: Hefner
authors.forename: Cecile
authors.initials: C
authors.lastname: Chartier
authors.forename: Jeng-Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Shelly
authors.initials: S
authors.lastname: Jiang
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Nayak
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Niyak
authors.forename: Frans A
authors.initials: FA
authors.lastname: Kuypers
authors.forename: Lisa
authors.initials: L
authors.lastname: Ma
authors.forename: Uma
authors.initials: U
authors.lastname: Sundram
authors.forename: Grace
authors.initials: G
authors.lastname: Wu
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Garcia
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Schrier
authors.forename: Jacquelyn J
authors.initials: JJ
authors.lastname: Maher
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Richard C
authors.initials: RC
authors.lastname: Mulligan
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
mesh_terms: D000818:Animals; D004921:Erythropoietin / Q000502:physiology*; D006400:Hematocrit; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D023421:Models, Animal; D011086:Polycythemia / Q000503:physiopathology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D012171:Retinal Vessels / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D040262:Receptors, Vascular Endothelial Growth Factor