@article{64fceb365b11463cbee55948cae1afcd,
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-1α-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.",
author = "Tam, {Betty Y Y} and Kevin Wei and Rudge, {John S.} and Jana Hoffman and Joceyln Holash and Park, {Sang Ki} and Jenny Yuan and Colleen Hefner and Cecile Chartier and Lee, {Jeng Shin} and Shelly Jiang and Niyak, {Nihar R.} and Kuypers, {Frans A.} and Lisa Ma and Uma Sundram and Grace Wu and Garcia, {Joseph A.} and Schrier, {Stanley L.} and Maher, {Jacquelyn J.} and Johnson, {Randall S.} and Yancopoulos, {George D.} and Mulligan, {Richard C.} and Kuo, {Calvin J.}",
note = "Funding Information: for HA-Flt1-His cDNA, A. Patterson for determination of arterial oxygen tension, A. Wagers for demonstrating parabiotic surgeries, M. Socolovsky for murine Epo, J. Zehnder for advice with real-time PCR, C. Koch for EF5 and EF5-specific antibodies, G. Molineux for permission to cite unpublished data and E. Yu for initial assistance. We are indebted to H.-P. Gerber and N. Ferrara for their gift of VegfaloxP/loxP mice, Y.-M. Lin and T. Wandless for synthesis of ZD4190 and the UCSF Liver Center (supported by NIH P30 DK26743) for providing core services. B.Y.Y.T. is a Fonds de la Recherche en Sant{\'e} du Qu{\'e}bec fellow. K.W. is supported by a Medical Scientist Training Program Grant to Stanford University. This work was supported by grants from the US National Institutes of Health (1 R01 CA95654-01 and 1 R01 HL074267-01) and the Department of Defense (DAMD17-02-1-0143) to C.J.K. and funds from Amgen Corporation (to R.J.K.). C.J.K. is a Burroughs Wellcome Foundation Scholar in the Pharmacological Sciences and a Kimmel Foundation Scholar.",
year = "2006",
month = jul,
doi = "10.1038/nm1428",
language = "English (US)",
volume = "12",
pages = "793--800",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "7",
}