VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis.
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.
Tam
Betty Y Y
BY
Division of Hematology, Stanford University School of Medicine, 269 Campus Drive, CCSR 1155, Stanford, California, 94305, USA.
Wei
Kevin
K
Rudge
John S
JS
Hoffman
Jana
J
Holash
Joceyln
J
Park
Sang-ki
SK
Yuan
Jenny
J
Hefner
Colleen
C
Chartier
Cecile
C
Lee
Jeng-Shin
JS
Jiang
Shelly
S
Nayak
Nihar R
NR
Niyak
Nihar R
NR
Kuypers
Frans A
FA
Ma
Lisa
L
Sundram
Uma
U
Wu
Grace
G
Garcia
Joseph A
JA
Schrier
Stanley L
SL
Maher
Jacquelyn J
JJ
Johnson
Randall S
RS
Yancopoulos
George D
GD
Mulligan
Richard C
RC
Kuo
Calvin J
CJ
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*
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