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, Kuo Calvin J
Division of Hematology, Stanford University School of Medicine, 269 Campus Drive, CCSR 1155, Stanford, California, 94305, USA.
Nat Med. 2006 Jul;12(7):793-800. doi: 10.1038/nm1428. Epub 2006 Jun 25.
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.
血管内皮生长因子（VEGF）在病理性血管生成和正常生理过程中发挥着关键作用。我们通过多种方法对VEGF进行高度抑制后观察到血细胞比容增加（60 - 75%），这些方法包括可溶性VEGF受体（VEGFR）胞外域的腺病毒表达、重组VEGF Trap蛋白以及VEGFR2选择性抗体DC101。红细胞生成增加（红细胞增多症）在小鼠和灵长类动物模型中均有发生，并且与VEGF角膜微囊血管生成的近乎完全中和相关。VEGF的高度抑制通过一种不依赖缺氧诱导因子-1α（HIF-1α）的机制诱导肝脏中促红细胞生成素（Epo，由Epo基因编码）的合成增加40倍以上，同时抑制肾脏Epo mRNA。利用Vegfa基因肝细胞特异性缺失和肝细胞-内皮细胞共培养的研究表明，VEGF的阻断通过干扰涉及肝细胞与内皮细胞相互作用的稳态VEGFR2依赖性旁分泌信号来诱导肝脏产生Epo。这些数据表明VEGF是肝脏Epo合成和红细胞生成之前未被怀疑的负调节因子，并提示Epo水平和红细胞增多症可能代表体内严格阻断VEGF的非侵入性替代标志物。
