Yamamoto Yasutoshi, Shiraishi Isao, Dai Ping, Hamaoka Kenji, Takamatsu Tetsuro
Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.
Anat Rec (Hoboken). 2007 Aug;290(8):958-73. doi: 10.1002/ar.20564.
The biological effects of vascular endothelial growth factor A (VEGF-A) are mediated by fetal liver kinase-1 (Flk-1) and fms-like tyrosine kinase-1 (Flt-1). In lung tissue, VEGF-A is diffusely expressed throughout the embryonic stages, whereas the development of vascular endothelial cells is not uniform. Noting the signaling properties of the two receptors, we hypothesized that Flk-1 and Flt-1 regulate the embryonic development of lung vasculature. We herein show the spatiotemporal expression and experimental inhibition of Flk-1 and Flt-1 of embryonic mouse lung tissue. When Flk-1 was predominantly expressed (embryonic day [E] 9.5-E13.5), then vascular endothelial cells actively proliferated. When Flt-1 was enhanced (E14.5-E16.5), these cells less actively proliferated, thereby constituting organized networks. The treatment of cultured lung buds (E11.5) with antisense oligonucleotides complementary to Flk-1 inhibited branching of capillaries and proliferation of endothelial cells. In contrast, the inhibition of Flt-1 promoted the branching of capillaries and enhanced proliferation of endothelial cells. Of interest, inhibition of Flt-1 promoted Flk-1 expression. These results suggest that the two VEGF-A receptors regulate pulmonary vascular development by modulating the VEGF-A signaling.
血管内皮生长因子A（VEGF-A）的生物学效应由胎儿肝激酶-1（Flk-1）和fms样酪氨酸激酶-1（Flt-1）介导。在肺组织中，VEGF-A在整个胚胎阶段均呈弥漫性表达，而血管内皮细胞的发育并不均匀。鉴于这两种受体的信号特性，我们推测Flk-1和Flt-1调节肺血管的胚胎发育。我们在此展示了胚胎小鼠肺组织中Flk-1和Flt-1的时空表达及实验性抑制情况。当Flk-1主要表达时（胚胎第[E]9.5天-E13.5天），血管内皮细胞积极增殖。当Flt-1增强时（E14.5天-E16.5天），这些细胞增殖活性降低，从而构成有组织的网络。用与Flk-1互补的反义寡核苷酸处理培养的肺芽（E11.5）可抑制毛细血管分支和内皮细胞增殖。相反，抑制Flt-1可促进毛细血管分支并增强内皮细胞增殖。有趣的是，抑制Flt-1可促进Flk-1表达。这些结果表明，两种VEGF-A受体通过调节VEGF-A信号传导来调控肺血管发育。
