VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis |
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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 Niyak 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 |
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Affiliation: | Division of Hematology, Stanford University School of Medicine, 269 Campus Drive, CCSR 1155, Stanford, California, 94305, USA. |
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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. |
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