Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations
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 c...
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2021-05-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/62155 |
| _version_ | 1811201401315917824 |
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| author | Wenqing Li Virginia Tran Iftach Shaked Belinda Xue Thomas Moore Rhonda Lightle David Kleinfeld Issam A Awad Mark H Ginsberg |
| author_facet | Wenqing Li Virginia Tran Iftach Shaked Belinda Xue Thomas Moore Rhonda Lightle David Kleinfeld Issam A Awad Mark H Ginsberg |
| author_sort | Wenqing Li |
| collection | DOAJ |
| description | 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 overexpression 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. |
| first_indexed | 2024-04-12T02:21:18Z |
| format | Article |
| id | doaj.art-85d99cab3cea493b919621e96939fdf1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:21:18Z |
| publishDate | 2021-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-85d99cab3cea493b919621e96939fdf12022-12-22T03:52:07ZengeLife Sciences Publications LtdeLife2050-084X2021-05-011010.7554/eLife.62155Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformationsWenqing Li0Virginia Tran1Iftach Shaked2Belinda Xue3Thomas Moore4Rhonda Lightle5David Kleinfeld6https://orcid.org/0000-0001-9797-4722Issam A Awad7Mark H Ginsberg8https://orcid.org/0000-0002-5685-5417Department of Medicine, University of California, San Diego, La Jolla, United StatesDepartment of Medicine, University of California, San Diego, La Jolla, United StatesDepartment of Physics, University of California, San Diego, La Jolla, United StatesDepartment of Medicine, University of California, San Diego, La Jolla, United StatesNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, University of Chicago School of Medicine and Biological Sciences, Chicago, United StatesNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, University of Chicago School of Medicine and Biological Sciences, Chicago, United StatesDepartment of Physics, University of California, San Diego, La Jolla, United States; Section of Neurobiology, University of California San Diego, La Jolla, United StatesNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, University of Chicago School of Medicine and Biological Sciences, Chicago, United StatesDepartment of Medicine, University of California, San Diego, La Jolla, United StatesMosaic 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 overexpression 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.https://elifesciences.org/articles/62155cerebral cavernous malformationsblood flow signalingangiogenesis |
| spellingShingle | Wenqing Li Virginia Tran Iftach Shaked Belinda Xue Thomas Moore Rhonda Lightle David Kleinfeld Issam A Awad Mark H Ginsberg Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations eLife cerebral cavernous malformations blood flow signaling angiogenesis |
| title | Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations |
| title_full | Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations |
| title_fullStr | Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations |
| title_full_unstemmed | Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations |
| title_short | Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations |
| title_sort | abortive intussusceptive angiogenesis causes multi cavernous vascular malformations |
| topic | cerebral cavernous malformations blood flow signaling angiogenesis |
| url | https://elifesciences.org/articles/62155 |
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