VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis

Betty Y Y Tam, Kevin Wei, John S. Rudge, Jana Hoffman, Joceyln Holash, Sang Ki Park, Jenny Yuan, Colleen Hefner, Cecile Chartier, Jeng Shin Lee, Shelly Jiang, Nihar R. Niyak, Frans A. Kuypers, Lisa Ma, Uma Sundram, Grace Wu, Joseph A. Garcia, Stanley L. Schrier, Jacquelyn J. Maher, Randall S. JohnsonGeorge D. Yancopoulos, Richard C. Mulligan, Calvin J. Kuo

Research output: Contribution to journalArticle

134 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)793-800
Number of pages8
JournalNature medicine
Volume12
Issue number7
DOIs
StatePublished - Jul 1 2006

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Tam, B. Y. Y., Wei, K., Rudge, J. S., Hoffman, J., Holash, J., Park, S. K., Yuan, J., Hefner, C., Chartier, C., Lee, J. S., Jiang, S., Niyak, N. R., Kuypers, F. A., Ma, L., Sundram, U., Wu, G., Garcia, J. A., Schrier, S. L., Maher, J. J., ... Kuo, C. J. (2006). VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nature medicine, 12(7), 793-800. https://doi.org/10.1038/nm1428