MAP2K1 Mutation in Zebrafish Endothelial Cells Causes Arteriovenous Shunts Preventable by MEK Inhibition
Objectives:. Arteriovenous malformation (AVM) is a congenital lesion with a nidus of irregular blood vessels connecting arteries to veins instead of a normal capillary bed. Somatic MAP2K1 activating mutations in endothelial cells cause extracranial AVM. The purpose of this study was to create a MAP2...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health/LWW
2023-03-01
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| Series: | Journal of Vascular Anomalies |
| Online Access: | http://journals.lww.com/10.1097/JOVA.0000000000000063 |
| _version_ | 1797870407575928832 |
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| author | Christopher L. Sudduth Nicola Blum Patrick J. Smits Yu Sheng Cheng Matthew P. Vivero Matthew P. Harris Nathan D. Lawson Arin K. Greene |
| author_facet | Christopher L. Sudduth Nicola Blum Patrick J. Smits Yu Sheng Cheng Matthew P. Vivero Matthew P. Harris Nathan D. Lawson Arin K. Greene |
| author_sort | Christopher L. Sudduth |
| collection | DOAJ |
| description | Objectives:. Arteriovenous malformation (AVM) is a congenital lesion with a nidus of irregular blood vessels connecting arteries to veins instead of a normal capillary bed. Somatic MAP2K1 activating mutations in endothelial cells cause extracranial AVM. The purpose of this study was to create a MAP2K1 AVM animal model using zebrafish and to test pharmacotherapy.
Methods:. Single-cell casper Tg(gata1a:DsRed) zebrafish embryos were injected with plasmid DNA (control [pTol2-Fli:GFP]; mutant [pTol2-Fli:GFP-kdrl:MAP2K1K57N]) and Tol2 transposase mRNA to mosaically express activated MAP2K1 in endothelial cells. Two cohorts of fish were examined: group 1 (n = 161) established phenotypes and group 2 (n = 126) tested MEK inhibition. Blood flow was visualized using DsRed fluorescence of erythrocytes. Embryos were imaged 72 hours postfertilization.
Results:. Group 1 exhibited abnormal arteriovenous shunts in 58 of 96 (60%) embryos expressing MAP2K1K57N in endothelial cells. Shunts occurred between the proximal aorta and common cardinal vein (n = 39; 67%) or between the major artery and vein within the trunk or tail (n = 19; 33%). Shunts were not present in control zebrafish (n = 65). MEK inhibition reduced shunt frequency caused by endothelial MAP2K1K57N expression in group 2 from 84% to 55% (0.2 μM) or 25% (0.4 μM) (P = .006).
Conclusions:. Zebrafish endothelial cells expressing mutant MAP2K1 form abnormal arteriovenous shunts supporting the causality of the variant in human AVMs. MEK inhibition reduced shunt formation validating its potential efficacy as a pharmacotherapeutic option for AVM. This zebrafish model may be used for further study of the etiopathogenesis of AVM as well as to test drugs. |
| first_indexed | 2024-04-10T00:28:06Z |
| format | Article |
| id | doaj.art-cdec7ed1106f41b0bd14e432b7a7b41d |
| institution | Directory Open Access Journal |
| issn | 2690-2702 |
| language | English |
| last_indexed | 2024-04-10T00:28:06Z |
| publishDate | 2023-03-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Journal of Vascular Anomalies |
| spelling | doaj.art-cdec7ed1106f41b0bd14e432b7a7b41d2023-03-15T08:08:43ZengWolters Kluwer Health/LWWJournal of Vascular Anomalies2690-27022023-03-0141e06310.1097/JOVA.0000000000000063202303000-00007MAP2K1 Mutation in Zebrafish Endothelial Cells Causes Arteriovenous Shunts Preventable by MEK InhibitionChristopher L. Sudduth0Nicola Blum1Patrick J. Smits2Yu Sheng Cheng3Matthew P. Vivero4Matthew P. Harris5Nathan D. Lawson6Arin K. Greene7a Department of Plastic and Oral Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusettsb Department of Orthopedic Research, Boston Children’s Hospital, Department of Genetics, Harvard Medical School, Boston, Massachusettsa Department of Plastic and Oral Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusettsa Department of Plastic and Oral Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusettsa Department of Plastic and Oral Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusettsb Department of Orthopedic Research, Boston Children’s Hospital, Department of Genetics, Harvard Medical School, Boston, Massachusettsc Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MAa Department of Plastic and Oral Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, MassachusettsObjectives:. Arteriovenous malformation (AVM) is a congenital lesion with a nidus of irregular blood vessels connecting arteries to veins instead of a normal capillary bed. Somatic MAP2K1 activating mutations in endothelial cells cause extracranial AVM. The purpose of this study was to create a MAP2K1 AVM animal model using zebrafish and to test pharmacotherapy. Methods:. Single-cell casper Tg(gata1a:DsRed) zebrafish embryos were injected with plasmid DNA (control [pTol2-Fli:GFP]; mutant [pTol2-Fli:GFP-kdrl:MAP2K1K57N]) and Tol2 transposase mRNA to mosaically express activated MAP2K1 in endothelial cells. Two cohorts of fish were examined: group 1 (n = 161) established phenotypes and group 2 (n = 126) tested MEK inhibition. Blood flow was visualized using DsRed fluorescence of erythrocytes. Embryos were imaged 72 hours postfertilization. Results:. Group 1 exhibited abnormal arteriovenous shunts in 58 of 96 (60%) embryos expressing MAP2K1K57N in endothelial cells. Shunts occurred between the proximal aorta and common cardinal vein (n = 39; 67%) or between the major artery and vein within the trunk or tail (n = 19; 33%). Shunts were not present in control zebrafish (n = 65). MEK inhibition reduced shunt frequency caused by endothelial MAP2K1K57N expression in group 2 from 84% to 55% (0.2 μM) or 25% (0.4 μM) (P = .006). Conclusions:. Zebrafish endothelial cells expressing mutant MAP2K1 form abnormal arteriovenous shunts supporting the causality of the variant in human AVMs. MEK inhibition reduced shunt formation validating its potential efficacy as a pharmacotherapeutic option for AVM. This zebrafish model may be used for further study of the etiopathogenesis of AVM as well as to test drugs.http://journals.lww.com/10.1097/JOVA.0000000000000063 |
| spellingShingle | Christopher L. Sudduth Nicola Blum Patrick J. Smits Yu Sheng Cheng Matthew P. Vivero Matthew P. Harris Nathan D. Lawson Arin K. Greene MAP2K1 Mutation in Zebrafish Endothelial Cells Causes Arteriovenous Shunts Preventable by MEK Inhibition Journal of Vascular Anomalies |
| title | MAP2K1 Mutation in Zebrafish Endothelial Cells Causes Arteriovenous Shunts Preventable by MEK Inhibition |
| title_full | MAP2K1 Mutation in Zebrafish Endothelial Cells Causes Arteriovenous Shunts Preventable by MEK Inhibition |
| title_fullStr | MAP2K1 Mutation in Zebrafish Endothelial Cells Causes Arteriovenous Shunts Preventable by MEK Inhibition |
| title_full_unstemmed | MAP2K1 Mutation in Zebrafish Endothelial Cells Causes Arteriovenous Shunts Preventable by MEK Inhibition |
| title_short | MAP2K1 Mutation in Zebrafish Endothelial Cells Causes Arteriovenous Shunts Preventable by MEK Inhibition |
| title_sort | map2k1 mutation in zebrafish endothelial cells causes arteriovenous shunts preventable by mek inhibition |
| url | http://journals.lww.com/10.1097/JOVA.0000000000000063 |
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