VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis.

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.

Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model.

Ovarian cancer is the most lethal gynecological malignancy and the fifth most common cause of cancer in women. It is characterized by diffuse peritoneal carcinomatosis and often by large volumes of i.p. ascites. Because vascular endothelial growth factor (VEGF), also known as vascular permeability factor, increases vascular permeability and stimulates endothelial cell growth, its role in ovarian cancer has been evaluated in a number of studies. However, questions remain regarding the ability of VEGF alone to cause ascites formation and the ability of VEGF blockade to inhibit the growth of disseminated cancer. We have used retroviral technology to create cell populations that overproduce VEGF and report that enforced expression of VEGF by ovarian carcinoma cells dramatically reduces the time to onset of ascites formation. In fact, even tumor-free peritoneal overexpression of VEGF, created by using adenoviral vectors, is sufficient to cause ascites to accumulate. We have found that systemic administration of the VEGF-Trap, a recently described high-affinity soluble decoy receptor for VEGF, prevents ascites accumulation and also inhibits the growth of disseminated cancer. Remarkably, much as is observed in s.c. tumor models, VEGF blockade results in dramatic remodeling of the blood vessels in disseminated ovarian carcinoma. The potent effects of the VEGF-Trap in reducing both ascites and tumor burden suggest that it will be of value in a regimen for treatment of women with ovarian cancer and ascites.