PUBLICATION

Vegfc/d-dependent regulation of the lymphatic vasculature during cardiac regeneration is influenced by injury context

Authors: Vivien, C.J., Pichol-Thievend, C., Sim, C.B., Smith, J.B., Bower, N.I., Hogan, B.M., Hudson, J.E., Francois, M., Porrello, E.R.
ID: ZDB-PUB-190828-13
Date: 2019
Source: NPJ Regenerative medicine 4: 18 (Journal)
Registered Authors: Hogan, Ben M.
Keywords: Angiogenesis, Cardiac regeneration
Datasets: GEO:GSE133129, GEO:GSE133130, GEO:GSE133131
MeSH Terms: none
PubMed: 31452940 Full text @ NPJ Regen Med

Abstract

The lymphatic vasculature mediates essential physiological functions including fluid homeostasis, lipid and hormone transport, and immune cell trafficking. Recent studies have suggested that promoting lymphangiogenesis enhances cardiac repair following injury, but it is unknown whether lymphangiogenesis is required for cardiac regeneration. Here, we describe the anatomical distribution, regulation, and function of the cardiac lymphatic network in a highly regenerative zebrafish model system using transgenic reporter lines and loss-of-function approaches. We show that zebrafish lacking functional vegfc and vegfd signaling are devoid of a cardiac lymphatic network and display cardiac hypertrophy in the absence of injury, suggesting a role for these vessels in cardiac tissue homeostasis. Using two different cardiac injury models, we report a robust lymphangiogenic response following cryoinjury, but not following apical resection injury. Although the majority of mutants lacking functional vegfc and vegfd signaling were able to mount a full regenerative response even in the complete absence of a cardiac lymphatic vasculature, cardiac regeneration was severely impaired in a subset of mutants, which was associated with heightened pro-inflammatory cytokine signaling. These findings reveal a context-dependent requirement for the lymphatic vasculature during cardiac growth and regeneration.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
DsRed	nz101Tg	standard conditions	Adult		bulbus arteriosus lymph vasculature	IHC	Fig. 2
DsRed	nz101Tg	standard conditions	Adult		bulbus arteriosus lymph vasculature	IHC	Fig. 1
DsRed	nz101Tg	standard conditions	Adult		cardiac ventricle lymph vasculature	IHC	Fig. 1
DsRed	nz101Tg	standard conditions	Adult		cardiac ventricle lymph vasculature	IHC	Fig. 2
DsRed	nz101Tg; s843Tg	standard conditions	Adult		bulbus arteriosus lymph vasculature	IHC	Fig. 1
DsRed	nz101Tg; s843Tg	standard conditions	Adult		cardiac ventricle lymph vasculature	IHC	Fig. 1
DsRed	nz101Tg; uq3bhTg; uq8bhTg	standard conditions	Adult		bulbus arteriosus lymph vasculature	IHC	Fig. 1
DsRed	nz101Tg; uq3bhTg; uq8bhTg	standard conditions	Adult		cardiac ventricle lymph vasculature	IHC	Fig. 1
DsRed	vegfc^{hu5055/hu5055}; vegfd^uq9bh/+; nz101Tg	standard conditions	Adult		bulbus arteriosus lymph vasculature	IHC	Fig. 2
DsRed	vegfc^{hu5055/hu5055}; vegfd^uq9bh/+; nz101Tg	standard conditions	Adult	Not Detected	cardiac ventricle lymph vasculature	IHC	Fig. 2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
vegfc^hu5055/+; vegfd^uq9bh/uq9bh; nz101Tg	standard conditions	Adult	cardiac ventricle lymph vasculature absent, abnormal	Fig. 2
vegfc^hu5055/+; vegfd^uq9bh/uq9bh; nz101Tg	standard conditions	Adult	cardiac ventricle lymph vasculature DsRed expression absent, abnormal	Fig. 2
vegfc^{hu5055/hu5055}; vegfd^uq9bh/+; nz101Tg	standard conditions	Adult	cardiac ventricle lymph vasculature absent, abnormal	Fig. 2
vegfc^{hu5055/hu5055}; vegfd^uq9bh/+; nz101Tg	standard conditions	Adult	cardiac ventricle lymph vasculature DsRed expression absent, abnormal	Fig. 2
vegfc^{hu5055/hu5055}; vegfd^uq9bh/uq9bh	standard conditions	Adult	cardiac muscle cell hypertrophic, abnormal	Fig. 3
vegfc^{hu5055/hu5055}; vegfd^uq9bh/uq9bh	standard conditions	Adult	cardiac muscle cell increased length, abnormal	Fig. 3
vegfc^{hu5055/hu5055}; vegfd^uq9bh/uq9bh	standard conditions	Adult	cardiac muscle cell increased volume, abnormal	Fig. 3
vegfc^{hu5055/hu5055}; vegfd^uq9bh/uq9bh	standard conditions	Adult	cardiac muscle cell increased width, abnormal	Fig. 3
vegfc^{hu5055/hu5055}; vegfd^uq9bh/uq9bh	standard conditions	Adult	cardiac ventricle hyperplastic, abnormal	Fig. 3
vegfc^{hu5055/hu5055}; vegfd^uq9bh/uq9bh	standard conditions	Adult	cardiac ventricle increased volume, abnormal	Fig. 3

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
hu5055		Point Mutation	vegfc
nz101Tg	Tg(-5.2lyve1b:DsRed)	Transgenic Insertion
s843Tg	Tg(kdrl:EGFP)	Transgenic Insertion
uq3bhTg	TgBAC(prox1a:KALTA4)	Transgenic Insertion
uq8bhTg	Tg(10xUAS:Venus)	Transgenic Insertion
uq9bh		Small Deletion	vegfd

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Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
nz101Tg
nz101Tg; s843Tg
nz101Tg; uq3bhTg; uq8bhTg
uq3bhTg
uq3bhTg; uq8bhTg
vegfc^{hu5055/hu5055}; vegfd^uq9bh/+; nz101Tg
vegfc^{hu5055/hu5055}; vegfd^uq9bh/uq9bh
vegfc^{hu5055/hu5055}; vegfd^uq9bh/uq9bh; nz101Tg
vegfc^hu5055/+; vegfd^uq9bh/uq9bh; nz101Tg

1 - 9 of 9

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Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-tpm	monoclonal		IgG1	Mouse
Ab2-fn	polyclonal			Rabbit

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP
KALTA4	EFG	KALTA4
Venus	EFG	Venus

Mapping

Vivien et al., 2019 ZDB-PUB-190828-13 PMID:31452940

Vegfc/d-dependent regulation of the lymphatic vasculature during cardiac regeneration is influenced by injury context

Vivien et al., 2019

ZDB-PUB-190828-13
PMID:31452940