Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden.
Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium.
Development. 2018 Jul 2;145(13):dev161182. doi: 10.1242/dev.161182.
Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.
血管系统的形成和稳态需要几种协调的细胞功能，但它们在发育过程中的精确相互作用及其对血管病变的相对重要性仍知之甚少。在这里，我们研究了 Cdc42 调节的内皮细胞功能及其在新生小鼠视网膜血管生成芽生和血管形态发生过程中的相关性。我们发现 Cdc42 是内皮尖端细胞选择、定向细胞迁移和丝状伪足形成所必需的，但对细胞增殖或凋亡是可有可无的。尽管 Cdc42 的缺失似乎通常与视网膜血管中的顶底极化和管腔形成兼容，但它会导致内皮轴向极化缺陷，并导致毛细血管和静脉中严重的血管畸形形成。在嵌合视网膜中追踪 Cdc42 耗尽的内皮细胞表明，这些毛细血管-静脉畸形的形成是由于细胞迁移缺陷所致，此时以正常速度增殖的内皮细胞无法在血管网络内重新分布。
