Department of Neurosurgery, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Transl Stroke Res. 2010 Jun;1(2):146-53. doi: 10.1007/s12975-010-0010-z.
Cerebral cavernous malformations (CCM) are characterized by abnormal dilated intracranial capillaries that predispose to hemorrhage. The development of some CCMs in humans has been attributed to mutations in the CCM1 genes. Currently, contradictory results have been generated regarding the vascular endothelial cell population changes in Ccm1 deficiency in zebrafish. We hypothesize that the inconsistent results simply reflect the spatial and temporal difference for the observed vascular endothelial cells during zebrafish embryonic development. Using high resolution images in vivo, we demonstrated that the loss of Ccm1 in zebrafish embryos leads to marked increases in apoptosis in vascular endothelium at the end stage of microvascular angiogenesis. In vivo zebrafish studies were further substantiated by in vitro findings in human endothelial cells that elucidated the biochemical pathways of CCM1 deficiency. We found that that loss of CCM1 in vitro promotes apoptosis through decreased activation of the integrin-linked kinase survival signaling pathway. In summary, Ccm1 has been identified as a key modulator in maintaining microvascular integrity during zebrafish embryonic angiogenesis.
脑内海绵状血管畸形（CCM）的特征是颅内异常扩张的毛细血管，容易导致出血。人类的一些 CCM 归因于 CCM1 基因突变。目前，关于斑马鱼 Ccm1 缺陷中的血管内皮细胞群体变化产生了相互矛盾的结果。我们假设不一致的结果只是反映了在斑马鱼胚胎发育过程中观察到的血管内皮细胞的时空差异。通过体内高分辨率图像，我们证明斑马鱼胚胎中 Ccm1 的缺失导致微血管生成末期血管内皮细胞凋亡的显著增加。体内斑马鱼研究进一步通过体外人内皮细胞的研究得到证实，该研究阐明了 CCM1 缺失的生化途径。我们发现，体外 CCM1 的缺失通过降低整合素连接激酶存活信号通路的激活来促进细胞凋亡。总之，Ccm1 已被确定为维持斑马鱼胚胎血管生成过程中小血管完整性的关键调节剂。
