VEGF‐D deficiency in mice does not affect embryonic or postnatal lymphangiogenesis but reduces lymphatic metastasis

Koch, Marta; Dettori, Daniela; Nuffelen, An Van; Souffreau, Joris; Marconcini, Lucia; Wallays, Goedele; Moons, Lieve; Bruyère, Françoise; Oliviero, Salvatore; Noël, Agnès; Foidart, Jean‐Michel; Carmeliet, Peter; Dewerchin, Mieke

doi:10.1002/path.2605

Cited by 36 publications

(39 citation statements)

References 58 publications

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“…VEGFC is a critical regulator of this process (6,7), but the VEGFC homolog VEGFD appears to play no required role in lymphatic development and has been linked instead to postnatal lymphangiogenesis (12). VEGFC and VEGFD contain N-and C-terminal extensions that are not found in VEGFA.…”

Section: Discussionmentioning

confidence: 99%

“…The finding that VEGFD proteolysis takes place independently of ADAMTS3 and CCBE1, both ex vivo and in vivo, demonstrates a remarkable difference in the regulation of these 2 lymphangiogenic factors that provides new insight into their distinct in vivo roles. Gain-of-function studies revealed that VEGFC and VEGFD have equally powerful lymphangiogenic effects in vivo (15,38), but genetic loss-of-function studies have only demonstrated a critical role for VEGFC during lymphatic development (6,12). If the primary role of ADAMTS3-CCBE1 processing is to lay down a roadmap of activated VEGFR3 ligand that LECs follow to create the primary lymphatic network, then this can only be accomplished by VEGFC.…”

Section: Activation Of Vegfr3 By Vegfc Requires N-and C-terminal Protmentioning

confidence: 99%

“…VEGFD is a second VEGFR3 ligand that is structurally and functionally homologous to VEGFC (10,11). Loss of VEGFD does not alter lymphatic development in mice or fish (12,13), but overexpression of either VEGFC or VEGFD drives lymphatic endothelial and vessel growth in mature animals (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

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Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD

Bui

Enis

Robciuc³

et al. 2016

Journal of Clinical Investigation

109

125

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Section: Discussionmentioning

confidence: 99%

Section: Activation Of Vegfr3 By Vegfc Requires N-and C-terminal Protmentioning

confidence: 99%

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Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD

Bui

Enis

Robciuc³

et al. 2016

Journal of Clinical Investigation

109

125

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“…Arterial remodeling or regrowth was assessed in the lung during pulmonary hypertension 35 and in the skin during healing of a full-thickness skin wound, 36 as detailed in the supplemental material.…”

Section: Phenotypic Analysismentioning

confidence: 99%

Notch3 Arg170Cys Knock-In Mice Display Pathologic and Clinical Features of the Neurovascular Disorder Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Wallays

Nuyens

Silasi‐Mansat

et al. 2011

ATVB

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Objective-Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset neurovascular disorder caused by stereotyped mutations in the NOTCH3 receptor. Elucidation of its pathobiology is still incomplete and remains a challenge, in part because the available preclinical mouse models to date do not reproduce the full spectrum of CADASIL pathology and clinical disease. Methods and Results-Here, we report a novel knock-in mouse with Arg170Cys substitution in murine Notch3, corresponding to the prevalent Arg169Cys substitution in CADASIL. The Notch3 Arg170Cys mice displayed late-onset, dominant CADASIL arteriopathy with typical granular osmiophilic material deposition and developed brain histopathology including thrombosis, microbleeds, gliosis, and microinfarction. Furthermore, Notch3Arg170Cys mice experienced neurological symptoms with motor defects such as staggering gait and limb paresis. The main symptoms are migraine with aura, psychiatric disturbances, and recurrent subcortical ischemic strokes causing motor disabilities, cognitive decline, dementia, and premature death. 2,3 The accompanying arteriopathy is characterized by the progressive degeneration of arterial smooth muscle cells (SMCs), deposition of electron-dense granular osmiophilic material (GOM) within the basal lamina of the SMCs and pericytes, and accumulation of the Notch3 extracellular cleavage product at the SMC membrane. 2-7 Although the arteriopathy is systemic, 8 the symptoms are mostly neurological. Brain pathology involves microbleeds, loss of myelin or axons, fibrillar gliosis, and lacunar infarcts in the white and deep gray matter. 2,3,9 CADASIL is caused by mutations in the transmembrane receptor Notch3, which is predominantly expressed in adult arterial SMCs. 10 -13 Pathogenic mutations stereotypically affect the number of cysteine residues in the epidermal growth factor-like repeats of the extracellular domain (ECD). [13][14][15] Thus far, more than 180 mutations are known, nearly 60% of which cluster in exon 4. 3,[13][14][15][16] In vitro and in vivo studies have highlighted a role of Notch3 in artery maturation, responses to vascular injury or ischemia, and regulation of SMC proliferation and apoptosis. [17][18][19][20][21][22][23][24][25] How the various Notch3 mutations effectuate arteriopathy and CADASIL disease development remains enigmatic.Previous approaches to generating a model of CADASIL include knock-in mice carrying the counterpart Arg141Cys CADASIL mutation (Arg142Cys in mouse) in the endogenous Notch3 gene, which failed, however, to develop any phenotype at all. 26 On the other hand, transgenic overexpression in mice of human or rat Notch3 carrying archetypal Notch3 mutations (Arg90Cys human Notch3, 27-30 Cys428Ser human Notch3, 31 Arg169Cys rat Notch3, 32 Cys455Arg and Arg1031Cys human Notch3 33 ) met with more success, with all models displaying the CADASIL arteriopathy. However, Here, we report a novel mutant mouse carrying an Arg170Cys knock-in mutation in the...

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“…Studies in humans have determined a direct correlation between VEGF-C/VEGF-D and lymphatic invasion, lymph node, and distant organ metastasis (6,9,11). Neutralization of VEGF-D with specific antibody or genetic deficiency of VEGF-D appears to suppress tumor metastasis in mice (12,13). VEGF-C has been shown to induce intercellular gaps that facilitate entry of tumor cells into the lumen of the vessels (14).…”

Section: Introductionmentioning

confidence: 99%

Genetic Ablation of SOX18 Function Suppresses Tumor Lymphangiogenesis and Metastasis of Melanoma in Mice

et al. 2012

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The lymphatic vasculature provides a major route for tumor metastasis and inhibiting neolymphangiogenesis induced by tumors can reduce metastasis in animal models. Developmental biology studies have identified the transcription factor SOX18 as a critical switch for lymphangiogenesis in the mouse embryo. Here, we show that SOX18 is also critical for tumor-induced lymphangiogenesis, and we show that suppressing SOX18 function is sufficient to impede tumor metastasis. Immunofluorescence analysis of murine tumor xenografts showed that SOX18 is reexpressed during tumor-induced neolymphangiogenesis. Tumors generated by implantation of firefly luciferase-expressing B16-F10 melanoma cells exhibited a reduced rate of metastasis to the regional draining lymph node in Sox18-deficient mice, as assessed by live bioluminescence imaging. Lower metastatic rates correlated with reduced tumoral lymphatic vessel density and diameter and with impaired drainage of peritumoral injected liposomes specific for lymph vessels from the sentinel lymph nodes. Overall, our findings suggested that SOX18 induction is a key step in mediating tumor lymphangiogenesis and metastasis, and they identify SOX18 as a potential therapeutic target for metastatic blockade. Cancer Res; 72(12);

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VEGF‐D deficiency in mice does not affect embryonic or postnatal lymphangiogenesis but reduces lymphatic metastasis

Abstract: ABSTRACT

Cited by 36 publications

References 58 publications

Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD

Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD

Notch3 Arg170Cys Knock-In Mice Display Pathologic and Clinical Features of the Neurovascular Disorder Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Genetic Ablation of SOX18 Function Suppresses Tumor Lymphangiogenesis and Metastasis of Melanoma in Mice

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