Journal
NATURE MEDICINE
Volume 12, Issue 7, Pages 793-800Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm1428
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Funding
- NCI NIH HHS [1 R01 CA95654-01] Funding Source: Medline
- NHLBI NIH HHS [1 R01 HL074267-01, K08 HL067154] Funding Source: Medline
- NIDDK NIH HHS [P30 DK026743, P30 DK26743] Funding Source: Medline
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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-1 alpha-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.
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