RT Journal Article
SR Electronic
T1 Abortive Intussusceptive Angiogenesis Causes Multi-Cavernous Vascular Malformations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.14.251744
DO 10.1101/2020.08.14.251744
A1 Wenqing Li
A1 Virginia Tran
A1 Iftach Shaked
A1 Belinda Xue
A1 Thomas Moore
A1 Rhonda Lightle
A1 David Kleinfeld
A1 Issam A. Awad
A1 Mark H. Ginsberg
YR 2020
UL http://biorxiv.org/content/early/2020/08/14/2020.08.14.251744.abstract
AB Mosaic inactivation of CCM2 in humans causes cerebral cavernous malformations (CCMs) containing adjacent dilated blood-filled multi-cavernous lesions. We used CRISPR-Cas9 mutagenesis to inactivate zebrafish ccm2 resulting in novel lethal multi-cavernous lesions in the embryonic caudal venous plexus (CVP) caused by obstruction of blood flow by intraluminal pillars. These pillars mimic intussusceptive angiogenesis; however, the pillars failed to fuse to split the pre-existing vessel in two. Abortive intussusceptive angiogenesis stemmed from mosaic inactivation of ccm2 leading to patchy klf2a over-expression and resulting aberrant flow signaling. Surviving adult fish manifested histologically-typical hemorrhagic CCM. Formation of mammalian CCM requires flow-regulated transcription factors, KLF2 and KLF4; fish CCM and the embryonic CVP lesion failed to form in klf2a null fish indicating a common pathogenesis with the mammalian lesion. These studies describe the first zebrafish CCM model and establish a mechanism that can explain the formation of characteristic multi-cavernous lesions.Subject terms Animal Models of Human Disease, Developmental Biology, Vascular Biology, PathophysiologyCompeting Interest StatementThe authors have declared no competing interest.CCMCerebral Cavernous MalformationsCRISPRclustered regularly interspaced short palindromic repeatsdpfdays post fertilizationgRNAguide RNAhpfhours post fertilizationNAnumerical apertureCUBICclear, unobstructed brain imaging cocktails and computational analysisCVPcaudal venous plexusCNScentral nervous systemRBCsred blood cellsH&EHematoxylin and eosin