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- Title
VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis.
- Authors
Tam, Betty Y Y; Wei, Kevin; Rudge, John S; Hoffman, Jana; Holash, Joceyln; Park, Sang-ki; Yuan, Jenny; Hefner, Colleen; Chartier, Cecile; Lee, Jeng-Shin; Jiang, Shelly; Nayak, Nihar R; Kuypers, Frans A; Ma, Lisa; Sundram, Uma; Wu, Grace; Garcia, Joseph A; Schrier, Stanley L; Maher, Jacquelyn J; Johnson, Randall S; Yancopoulos, George D; Mulligan, Richard C; Kuo, Calvin J
- 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.
- Publication
Nature medicine, 2006, Vol 12, Issue 7, p793
- ISSN
1078-8956
- Publication type
Journal Article
- DOI
10.1038/nm1428