Breier G, Clauss M, Risau W
Max-Planck-Institut für physiologische und klinische Forschung, Bad Nauheim, Germany.
Dev Dyn. 1995 Nov;204(3):228-39. doi: 10.1002/aja.1002040303.
Vascular endothelial growth factor (VEGF) is a candidate regulator of blood vessel growth during embryonic development and in tumors. To evaluate the role of VEGF receptor-1/flt-1 (VEGFR1/flt-1) in the development of the vascular system, we have characterized the murine homolog of the human flt-1 gene and have analyzed its expression pattern during mouse embryogenesis. Receptor binding studies using transfected COS cells revealed that the murine flt-1 gene encodes a high affinity receptor for VEGF. The apparent Kd for VEGF binding, as determined by Scatchard analysis, was 114 pM, demonstrating that VEGFR1/flt-1 has a higher affinity to VEGF than VEGF receptor-2/flk-1 (VEGFR2/flk-1). By in situ hybridization, VEGFR1/flt-1 was detected in the yolk sac mesoderm already at the early stages of vascular development, while the receptor ligand was expressed in the entire endoderm of 7.5-day mouse embryos. A comparison with VEGFR2/flk-1 showed that the two receptors shared a common expression domain in the yolk sac mesoderm, but were expressed at different sites in the ectoplacental cone. The differential expression of the two VEGF receptors persisted in the developing placenta, where VEGFR1/flt-1 mRNA was detected in the spongiotrophoblast layer, whereas VEGFR2/flk-1 transcripts were present in the labyrinthine layer which is the site of VEGF expression. In the embryo proper, VEGFR1/flt-1 mRNA was specifically localized in blood vessels and capillaries of the developing organs, closely resembling the pattern of VEGFR2/flk-1 transcript distribution. In the developing brain, the expression of VEGF receptors in the perineural capillary plexus and in capillary sprouts which have invaded the neuro-ectoderm correlated with endothelial cell proliferation and brain angiogenesis. The data are consistent with the hypothesis that VEGF and its receptors have an important function both in the differentiation of the endothelial lineage and in the neovascularization of developing organs, and act in a paracrine fashion.
血管内皮生长因子（VEGF）是胚胎发育和肿瘤血管生成过程中血管生长的候选调节因子。为了评估VEGF受体-1/flt-1（VEGFR1/flt-1）在血管系统发育中的作用，我们对人flt-1基因的小鼠同源物进行了表征，并分析了其在小鼠胚胎发育过程中的表达模式。使用转染的COS细胞进行的受体结合研究表明，小鼠flt-1基因编码一种VEGF的高亲和力受体。通过Scatchard分析确定的VEGF结合的表观解离常数（Kd）为114 pM，表明VEGFR1/flt-1对VEGF的亲和力高于VEGF受体-2/flk-1（VEGFR2/flk-1）。通过原位杂交，在血管发育早期的卵黄囊间皮中就检测到了VEGFR1/flt-1，而受体配体在7.5天小鼠胚胎的整个内胚层中表达。与VEGFR2/flk-1的比较表明，这两种受体在卵黄囊间皮中有共同的表达域，但在胎盘外锥体的不同部位表达。两种VEGF受体的差异表达在发育中的胎盘中持续存在，在滋养层海绵层中检测到VEGFR1/flt-1 mRNA，而VEGFR2/flk-1转录本存在于VEGF表达部位的迷路层中。在胚胎本身，VEGFR1/flt-1 mRNA特异性地定位于发育中器官的血管和毛细血管中，与VEGFR2/flk-1转录本的分布模式非常相似。在发育中的大脑中，神经周围毛细血管丛和侵入神经外胚层的毛细血管芽中VEGF受体的表达与内皮细胞增殖和脑血管生成相关。这些数据与以下假设一致，即VEGF及其受体在内皮细胞谱系的分化和发育中器官的新生血管形成中都具有重要功能，并以旁分泌方式发挥作用。
