Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea K S, Powell-Braxton L, Hillan K J, Moore M W
Department of Cardiovascular Research, Genentech Inc., South San Francisco, California 94080, USA.
Nature. 1996 Apr 4;380(6573):439-42. doi: 10.1038/380439a0.
Angiogenesis is required for a wide variety of physiological and pathological processes. The endothelial cell-specific mitogen vascular endothelial growth factor (VEGF) is a major mediator of pathological angiogenesis. Also, the expression of VEGF and its two receptors, Flt-1 and Flk-1/KDR, is related to the formation of blood vessels in mouse and rat embryos. Mice homozygous for mutations that inactivate either receptor die in utero between days 8.5 and 9.5. However, ligand(s) other than VEGF might activate such receptors. To assess the role of VEGF directly, we disrupted the VEGF gene in embryonic stem cells. Here we report the unexpected finding that loss of a single VEGF allele is lethal in the mouse embryo between days 11 and 12. Angiogenesis and blood-island formation were impaired, resulting in several developmental anomalies. Furthermore, VEGF-null embryonic stem cells exhibit a dramatically reduced ability to form tumours in nude mice.
血管生成是多种生理和病理过程所必需的。内皮细胞特异性促有丝分裂原血管内皮生长因子（VEGF）是病理性血管生成的主要介质。此外，VEGF及其两种受体Flt-1和Flk-1/KDR的表达与小鼠和大鼠胚胎血管的形成有关。因突变而使任一受体失活的纯合子小鼠在子宫内8.5至9.5天之间死亡。然而，除VEGF之外的其他配体可能激活此类受体。为了直接评估VEGF的作用，我们在胚胎干细胞中破坏了VEGF基因。在此我们报告了一个意外发现，即单个VEGF等位基因的缺失在小鼠胚胎11至12天之间是致命的。血管生成和血岛形成受损，导致多种发育异常。此外，VEGF基因缺失的胚胎干细胞在裸鼠中形成肿瘤的能力显著降低。
