Decreased expression of neuropilin-1 as a novel key factor contributing to peripheral microvasculopathy and defective angiogenesis in systemic sclerosis

Romano, Eloisa; Chora, Inês; Manetti, Mirko; Mazzotta, Celestina; Rosa, Irene; Bellando-Randone, Silvia; Blagojević, Jelena; Soares, Raquel; Avouac, Jérôme; Allanore, Yannick; Ibba‐Manneschi, Lidia; Matucci‐Cerinic, Marco; Guiducci, Serena

doi:10.1136/annrheumdis-2015-207483

Cited by 41 publications

(38 citation statements)

References 45 publications

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“…Previous studies have demonstrated that treatment with sera from patients with SSc impairs the angiogenic performance of H-dMVECs in vitro 29 39 40. Nevertheless, whether these antiangiogenic effects may be in part related to the induction of the EndoMT process has never been investigated.…”

Section: Resultsmentioning

confidence: 99%

“…Skin biopsies were processed as previously described 28 29. Patient characteristics are summarised in online supplementary table S1.…”

Section: Methodsmentioning

confidence: 99%

“…Patient characteristics are summarised in online supplementary table S1. Adherent cells were detached and subjected to CD31 immunomagnetic isolation by incubation with anti-CD31 conjugated-microbeads 28 29. Isolated cells were further identified as ECs by labelling with anti-factor VIII-related antigen (vWF) and anti-CD105, followed by reprobing with anti-CD31 antibodies (see online supplementary figure S1).…”

Section: Methodsmentioning

confidence: 99%

“…First-strand cDNA synthesis and mRNA quantification by SYBR Green real-time PCR were performed as reported elsewhere 29. For predesigned oligonucleotide primer pairs, refer to the online supplementary material.…”

Section: Methodsmentioning

confidence: 99%

“…Whole-cell protein lysates from dMVECs were subjected to immunoblot analysis as described elsewhere 29. For details on primary antibodies against CD31, VE-cadherin, α-SMA, S100A4/FSP1, type I collagen, Snail1, Friend leukaemia integration-1 (Fli1), urokinase-type plasminogen activator receptor (uPAR) domain 1 (D1) and domain 2 and α-tubulin, refer to the online supplementary material.…”

Section: Methodsmentioning

confidence: 99%

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Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis

et al. 2017

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Section: Resultsmentioning

confidence: 99%

“…Skin biopsies were processed as previously described 28 29. Patient characteristics are summarised in online supplementary table S1.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis

et al. 2017

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Histone Deacetylase 5 Is Overexpressed in Scleroderma Endothelial Cells and Impairs Angiogenesis via Repression of Proangiogenic Factors

Tsou

Wren

Amin

et al. 2016

Arthritis & Rheumatology

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Objective Vascular dysfunction represents a disease initiating event in scleroderma (SSc). Recent data suggest that epigenetic dysregulation impairs normal angiogenesis and can result in abnormal blood vessel growth patterns. Histone deacetylases (HDACs) control endothelial cell (EC) proliferation and regulate EC migration. Specifically, HDAC5 appears to be anti-angiogenic. We hypothesized that HDAC5 contributes to impaired angiogenesis in SSc by repressing pro-angiogenic factors in ECs. Methods Dermal ECs were isolated from patients with diffuse cutaneous SSc and healthy controls. Angiogenesis was assessed by an in vitro Matrigel tube formation assay. An assay for transposase-accessible chromatin using sequencing (ATAC-seq) was performed to assess and localize genome-wide effects of HDAC5 knockdown on chromatin accessibility. Results The expression of HDAC5 was significantly increased in SSc ECs compared to normal ECs. Silencing of HDAC5 in SSc ECs restored normal angiogenesis. HDAC5 knockdown followed by ATAC-seq in SSc ECs identified key HDAC5-regulated genes involved in angiogenesis and fibrosis, such as CYR61, PVRL2, and FSTL1. Simultaneous knockdown of HDAC5 with either CYR61, PVRL2, or FSTL1 inhibited angiogenesis in SSc ECs while overexpression of these genes individually led to increase in tube formation in Matrigel assay, suggesting that these genes play functional roles in impairing angiogenesis in SSc. Conclusions Several novel HDAC5-target genes associated with impaired angiogenesis were identified in SSc ECs by ATAC-seq. This study provides a link between epigenetic regulation and impaired angiogenesis in SSc, and identifies a novel mechanism for dysregulated angiogenesis that characterizes this disease.

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ERG Regulates Lymphatic Vessel Specification Genes and Its Deficiency Impairs Wound Healing‐Associated Lymphangiogenesis

Yamashita,

Kaplan,

Chakraborty

et al. 2024

Arthritis & Rheumatology

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ObjectiveRarefaction of blood and lymphatic vessels in the skin has been reported in SSc (systemic sclerosis, scleroderma). ERG and FLI1 are important regulators of angiogenesis, but their role in lymphatic vasculature is less known. The goal of this study was to determine the role of ERG and FLI1 in postnatal lymphangiogenesis and SSc lymphatic system defects.MethodsImmunofluorescence was used to detect ERG and FLI1 in SSc and healthy control (HC) skin biopsies. Transcriptional analysis of ERG or FLI1 silenced human dermal lymphatic endothelial cells (LECs) was performed using microarrays. Effects of ERG/FLI1 deficiency on in vitro tubulogenesis in human dermal LECs was examined using a Matrigel assay. Erg and Fli1 endothelial specific knockouts and Erg lymphatic specific knockouts were generated to examine vessel regeneration in mice.ResultsERG and FLI1 protein levels were reduced in the blood and lymphatic vasculature in SSc skin biopsies. ERG was shown to regulate genes involved in lymphatic vessel specification, including VEGFR3/FLT4, LYVE‐1, SOX18, and PROX1, while FLI1 enhanced the function of ERG. ERG/FLT4 pathway regulated in vitro tubulogenesis in human LECs. Deficiency of Erg or Fli1 similarly impaired the function of blood vessels in mice. However, only Erg deficiency affected the regeneration of lymphatic vessels during wound healing.ConclusionERG and FLI1 are essential regulators of blood and lymphatic vessel regeneration. Deficiency of ERG and FLI1 in SSc endothelial cells, may contribute to impairment of blood and lymphatic vasculature in SSc patientsimage

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Decreased expression of neuropilin-1 as a novel key factor contributing to peripheral microvasculopathy and defective angiogenesis in systemic sclerosis

Abstract: In SSc, NRP1 deficiency may be an additional factor in the perturbed VEGF-A/VEGFR-2 system contributing to peripheral microvasculopathy and defective angiogenesis.

Cited by 41 publications

References 45 publications

Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis

Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis

Histone Deacetylase 5 Is Overexpressed in Scleroderma Endothelial Cells and Impairs Angiogenesis via Repression of Proangiogenic Factors

ERG Regulates Lymphatic Vessel Specification Genes and Its Deficiency Impairs Wound Healing‐Associated Lymphangiogenesis

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