Details

Autor(en) / Beteiligte

• Kuo, Calvin J
• 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

Titel

VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis

Ist Teil von

• Nature medicine, 2006-07, Vol.12 (7), p.793-800

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2006

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.