Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations
- University of California, San Diego, United States
- University of Chicago, United States
Abstract
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 induce mosaic inactivation of zebrafish ccm2 resulting in a novel lethal multi-cavernous lesion in the embryonic caudal venous plexus (CVP) caused by obstruction of blood flow by intraluminal pillars. These pillars mimic those that mediate intussusceptive angiogenesis; however, in contrast to the normal process, 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 resultant aberrant flow signaling. Surviving adult fish manifested histologically-typical hemorrhagic CCM. Formation of mammalian CCM requires the flow-regulated transcription factor KLF2; 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 a zebrafish CCM model and establish a mechanism that can explain the formation of characteristic multi-cavernous lesions.
Data availability
Raw Phenotype counts have been provided in figures and and figure legends.
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Author details
Funding
National Heart, Lung, and Blood Institute (HL 139947)
- Mark H Ginsberg
National Institutes of Health (NS 92521)
- Thomas Moore
- Rhonda Lightle
- Issam A Awad
- Mark H Ginsberg
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#S14135 ) of the University of California San Diego.
Copyright
© 2021, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations
eLife 10:e62155.
https://doi.org/10.7554/eLife.62155
