Ccm1 Assures Microvascular Integrity During Angiogenesis
- 113 Downloads
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.
KeywordsCerebral cavernous malformation Angiogenesis Intersegmental vessels Apoptosis Vascular endothelial cell
We thank Chris Carr and Betty Chen at UMMC Neurosurgery, Hal Dietz, Richard Clatterbuck, and Sharmila Basu at Johns Hopkins University for their invaluable technical help and discussion during the experiments and in the preparation of this manuscript.
- 5.Jin S-W, Herzog W, Santoro MM, Mitchell TS, Frantsve J, Jungblut B, Beis D, Scott IC, D'Amico LA, Ober EA, Verkade H, Field HA, Chi NC, Wehman AM, Baier H, Stainier DYR (2007) A transgene-assisted genetic screen identifies essential regulators of vascular development in vertebrate embryos. Dev Biol 307:29–42PubMedCrossRefGoogle Scholar
- 27.Wang YG, Liu HT, Zhang YM, Ma DL (1999) Cdna cloning and expression of an apoptosis-related gene, human tfar-15 gene. Science in China C Life Sci 29:331–336Google Scholar