A dual role for
            <i>Tbx1</i>
            in cardiac lymphangiogenesis through genetic interaction with
            <i>Vegfr3</i>

Martucciello, Stefania; Turturo, Maria Giuseppina; Bilio, Marchesa; Cioffi, Sara; Chen, Li; Baldini, Antonio; Illingworth, Elizabeth

doi:10.1096/fj.201902202r

Cited by 12 publications

(15 citation statements)

References 46 publications

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“…Thus, the distribution of Tbx1 -fated cells likely reflects a wave of activation that expands in different regions of the growing brain vascular network, rather than the deployment of Tbx1 -expressing EC progenitors and their progeny. The fact that the brain vascular phenotype was only detectable after E13.5, is consistent with the interpretation that critical TBX1 functions are in differentiated ECs and not in EC progenitors, in contrast, for example to the role of TBX1 in cardiac lymphatic vessels (Martucciello et al, 2020).…”

Section: Discussionsupporting

confidence: 86%

“…We asked whether over-expression of Vegfr3 in the Tbx1 expression domain would rescue the brain vessel abnormalities of Tbx1 mutant embryos. To this end, we crossed Tbx1 Cre/+ mice with mice carrying a single copy of a Cre-activatable murine Vegfr3 transgene, TgVegfr3 mice (Martucciello et al, 2020). We then intercrossed mice with the genotypes Tbx1 Cre/+ ;TgVegfr3 and Tbx1 lacZ/+ and measured brain vessel density and filopodial density in E18.5 embryos with the following genotypes: Tbx1 +/+ , Tbx1 Cre/+ , Tbx1 Cre/lacZ , TgVegfr3; Tbx1 Cre/+ and TgVegfr3; Tbx1 Cre/lacZ that were immunostained with anti-GLUT1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

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VEGFR3 modulates brain microvessel branching in a mouse model of 22q11.2 deletion syndrome

Cioffi

Flore

Martucciello

et al. 2022

Preprint

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The loss of a single copy of TBX1 accounts for most of the clinical signs and symptoms of 22q11.2 deletion syndrome (22q11.2DS), a common genetic disorder that is characterized by multiple congenital anomalies and brain-related clinical problems, some of which likely have vascular origins. Tbx1 mutant mice have brain vascular anomalies, thus making them a useful model to gain insights into the brain disorders associated with the human disease. Here, we found that Tbx1 has a dynamic expression pattern in brain endothelial cells (ECs), including tip cells, during early vascularization, but it is not expressed in EC progenitors. Its main morphogenetic function in the brain is to regulate negatively filopodia biogenesis and vessel branching. Because of similar phenotypes reported for Vegfr3 loss of function, we pursued a mouse genetic approach to test TBX1- VEGFR3 interaction through gain and loss of function experiments. Vegfr3 is expressed in brain ECs with extensive overlap with Tbx1 expression. We demonstrate that inactivating Vegfr3 in the Tbx1 expression domain in a Tbx1 mutant background enhances vessel branching and filopodia formation to a greater extent than that observed in the individual mutants. Furthermore, using a mouse transgenic line, we show that increasing Vegfr3 expression in the Tbx1 expression domain fully rescued the vessel branching and filopodia phenotypes caused by Tbx1 loss of function. Similar results were obtained using an in vitro model of endothelial tubulogenesis. Overall, these results provide genetic evidence that Vegfr3 is a regulator of early vessel branching and filopodia formation in the brain, and is a likely critical effector of the brain vascular phenotype caused by Tbx1 loss of function.

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Section: Discussionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

VEGFR3 modulates brain microvessel branching in a mouse model of 22q11.2 deletion syndrome

Cioffi

Flore

Martucciello

et al. 2022

Preprint

Self Cite

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“…Although our recent data demonstrate that angiotensin II markedly increases VEGFR‐3 expression and lymphangiogenesis in mouse LECs though the angiotensin type I receptor, 30 the precise mechanisms by which pressure overload regulates VEGF‐C or VEGFR‐3 expression in LECs remain unclear. A previous study has shown that Tbx1, a member of the T‐box family of transcription factors, can upregulate VEGFR‐3 expression in endothelial cells by binding to an enhancer element within the Vegfr‐3 gene 31 . This prompted us to examine Tbx1 expression in TAC‐operated hearts.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study has shown that Tbx1, a member of the T-box family of transcription factors, can upregulate VEGFR-3 expression in endothelial cells by binding to an enhancer element within the Vegfr-3 gene. 31 This prompted us to examine Tbx1 expression in TACoperated hearts. We found that there were similar expression patterns between Tbx1 and VEGF-C or VEGFR-3 during the transition from adaptive cardiac hypertrophy to TAC-induced HF (supplementary material online, Figure S4C), suggesting that Tbx1 may be involved in regulating VEGF-C or VEGFR-3 expression in the heart.…”

Section: Discussionmentioning

confidence: 99%

VEGF‐C/VEGFR‐3 axis protects against pressure‐overload induced cardiac dysfunction through regulation of lymphangiogenesis

Lin

Zhang

Bai

et al. 2021

Clinical & Translational Med

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Schematic illustration for VEGF-C-VEGFR-3 signaling-mediated cardiac lymphangiogenesis to improve TAC-induced cardiac dysfunction. Persistent pressure overload reduces VEGF-C and VEGFR-3 expression and inactivates the downstream signals (ATK/ERK, CaNA/NFATc1/FOXC2, and CX43), which inhibits cardiac lymphangiogenesis and increases cardiac edema thereby leading to cardiac hypertrophy, fibrosis, inflammation, apoptosis, and contractile dysfunction in mice. Conversely, stimulation of cardiac lymphangiogenesis by application of VEGF-C156S prevents these effects, and this represents a new therapeutic pathway for improving cardiac dysfunction after pressure overload.

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“…The heart has an extensive lymphatic vessel network comprising a heterogeneous origin and signaling that regulates its development [ 230 , 231 , 232 , 233 , 234 , 235 ]. In a mouse MI model [ 236 ], cardiac lymphatic vessel impairment leads to interstitial fluid accumulation and myocardial fibrosis progression due to increased interstitial fluid pressure that might induce CF activation through mechanical stress within the ECM [ 237 ].…”

Section: Cardiac Lymphaticsmentioning

confidence: 99%

The Pathogenesis of Cardiac Fibrosis: A Review of Recent Progress

Maruyama

Imanaka‐Yoshida

2022

IJMS

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Fibrosis is defined as the excessive deposition of extracellular matrix (ECM) proteins in the interstitium. It is an essential pathological response to chronic inflammation. ECM protein deposition is initially protective and is critical for wound healing and tissue regeneration. However, pathological cardiac remodeling in excessive and continuous tissue damage with subsequent ECM deposition results in a distorted organ architecture and significantly impacts cardiac function. In this review, we summarized and discussed the histologic features of cardiac fibrosis with the signaling factors that control it. We evaluated the origin and characteristic markers of cardiac fibroblasts. We also discussed lymphatic vessels, which have become more important in recent years to improve cardiac fibrosis.

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A dual role for Tbx1 in cardiac lymphangiogenesis through genetic interaction with Vegfr3

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 12 publications

References 46 publications

VEGFR3 modulates brain microvessel branching in a mouse model of 22q11.2 deletion syndrome

VEGFR3 modulates brain microvessel branching in a mouse model of 22q11.2 deletion syndrome

VEGF‐C/VEGFR‐3 axis protects against pressure‐overload induced cardiac dysfunction through regulation of lymphangiogenesis

The Pathogenesis of Cardiac Fibrosis: A Review of Recent Progress

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