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FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms

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Title: FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms
Authors: Richard M Monaghan, Richard W Naylor, Daisy Flatman, Paul R Kasher, Simon G Williams, Bernard D Keavney
Source: Cardiovasc Res
Monaghan, R M, Naylor, R W, Flatman, D, Kasher, P R, Williams, S G & Keavney, B D 2024, 'FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms', Cardiovascular research, vol. 120, no. 10, cvae104, pp. 1164-1176. https://doi.org/10.1093/cvr/cvae104
Publisher Information: Oxford University Press (OUP), 2024.
Publication Year: 2024
Subject Terms: 0301 basic medicine, Cells, Endothelial Cells/metabolism, Endoplasmic Reticulum, Zebrafish/genetics, 03 medical and health sciences, Primary lymphoedema, Zebrafish Proteins/genetics, Human Umbilical Vein Endothelial Cells, Animals, Humans, Developmental, Genetic Predisposition to Disease, Vascular Endothelial Growth Factor Receptor-3/metabolism, Lymphedema, FLT4, Human Umbilical Vein Endothelial Cells/metabolism, Endoplasmic Reticulum/metabolism, Cells, Cultured, Zebrafish, Congenital heart disease, 0303 health sciences, Cultured, Endothelial Cells, Gene Expression Regulation, Developmental, Tetralogy of Fallot/genetics, Zebrafish Proteins, Vascular Endothelial Growth Factor Receptor-3, 3. Good health, Phenotype, Gene Expression Regulation, Mutation, Proteostasis, Tetralogy of Fallot, Original Article, Developmental pleiotropy, VEGFR3, Lymphedema/genetics, Signal Transduction
Description: Aims Rare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease. The distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. The phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development. Methods and results In this study, we show that FLT4 variants identified in patients with TOF, when expressed in primary human endothelial cells, cause aggregation of FLT4 protein in the perinuclear endoplasmic reticulum, activating proteostatic and metabolic signalling, whereas lymphoedema-associated FLT4 variants and wild-type (WT) FLT4 do not. FLT4 TOF variants display characteristic gene expression profiles in key developmental signalling pathways, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of proteostatic signalling abrogates these effects, identifying potential avenues for therapeutic intervention. Depletion of flt4 in zebrafish caused cardiac phenotypes of reduced heart size and altered heart looping. These phenotypes were rescued with coinjection of WT human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants. Conclusion Taken together, we identify a pathogenic mechanism for FLT4 variants predisposing to TOF that is distinct from the known dominant negative mechanism of Milroy-causative variants. FLT4 variants give rise to conditions of the two circulatory subdivisions of the vascular system via distinct developmental pleiotropic molecular mechanisms.
Document Type: Article
Other literature type
Language: English
ISSN: 1755-3245
0008-6363
DOI: 10.1093/cvr/cvae104
Access URL: https://pubmed.ncbi.nlm.nih.gov/38713105
https://research.manchester.ac.uk/en/publications/8c40ed3a-6c44-44cc-856f-46aef161c8b3
https://doi.org/10.1093/cvr/cvae104
https://research.manchester.ac.uk/en/publications/8c40ed3a-6c44-44cc-856f-46aef161c8b3
http://www.scopus.com/inward/record.url?scp=85200464249&partnerID=8YFLogxK
https://doi.org/10.1093/cvr/cvae104
Rights: CC BY NC
URL: http://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
Accession Number: edsair.doi.dedup.....d0ebc235bb5108a3ee20b38160dae6d3
Database: OpenAIRE
Description
Abstract:Aims Rare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease. The distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. The phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development. Methods and results In this study, we show that FLT4 variants identified in patients with TOF, when expressed in primary human endothelial cells, cause aggregation of FLT4 protein in the perinuclear endoplasmic reticulum, activating proteostatic and metabolic signalling, whereas lymphoedema-associated FLT4 variants and wild-type (WT) FLT4 do not. FLT4 TOF variants display characteristic gene expression profiles in key developmental signalling pathways, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of proteostatic signalling abrogates these effects, identifying potential avenues for therapeutic intervention. Depletion of flt4 in zebrafish caused cardiac phenotypes of reduced heart size and altered heart looping. These phenotypes were rescued with coinjection of WT human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants. Conclusion Taken together, we identify a pathogenic mechanism for FLT4 variants predisposing to TOF that is distinct from the known dominant negative mechanism of Milroy-causative variants. FLT4 variants give rise to conditions of the two circulatory subdivisions of the vascular system via distinct developmental pleiotropic molecular mechanisms.
ISSN:17553245
00086363
DOI:10.1093/cvr/cvae104