2. Academic Validation
  3. MAP2K1 Mutation in Zebrafish Endothelial Cells Causes Arteriovenous Shunts Preventable by MEK Inhibition

MAP2K1 Mutation in Zebrafish Endothelial Cells Causes Arteriovenous Shunts Preventable by MEK Inhibition

  • J Vasc Anom (Phila). 2023 Mar;4(1):e063. doi: 10.1097/jova.0000000000000063.
Christopher L Sudduth 1,  Nicola Blum 2,  Patrick J Smits 1,  Yu Sheng Cheng 1,  Matthew P Vivero 1,  Matthew P Harris 2,  Nathan D Lawson 3,  Arin K Greene 1
Affiliations

Affiliations

  • 1 Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 2 Department of Orthopedic Research, Boston Children's Hospital, Department of Genetics, Harvard Medical School, Boston, Massachusetts.
  • 3 Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA.
PMID: 40969398 DOI: 10.1097/jova.0000000000000063
Abstract

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.

Keywords

AVM; MAP2K1; MEK; arteriovenous malformation; shunt; trametinib; vascular; zebrafish.

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