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

IF 11.4 1区医学 Q1 RHEUMATOLOGY Arthritis & Rheumatology Pub Date : 2024-07-04 DOI:10.1002/art.42944

Takashi Yamashita, Ulas Kaplan, Adri Chakraborty, Grace Marden, Sami Gritli, Daniel Roh, Andreea Bujor, Marcin Trojanowski, Giovanni Ligresti, Jeffrey L. Browning, Maria Trojanowska

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Abstract

Objective

Rarefaction of blood and lymphatic vessels in the skin has been reported in systemic sclerosis (SSc) (scleroderma). E26 transformation–specific–related factor (ERG) and Friend leukemia virus–induced erythroleukemia 1 (FLI-1) are important regulators of angiogenesis, but their role in lymphatic vasculature is lesser known. The goal of this study was to determine the role of ERG and FLI-1 in postnatal lymphangiogenesis and SSc lymphatic system defects.

Methods

Immunofluorescence was used to detect ERG and FLI-1 in skin biopsy samples from patients with SSc and healthy controls. Transcriptional analysis of ERG or FLI-1–silenced human dermal lymphatic endothelial cells (LECs) was performed using microarrays. Effects of ERG and FLI-1 deficiency on in vitro tubulogenesis in human dermal LECs were examined using a Matrigel assay. ERG and FLI-1 endothelial–specific knockouts and ERG lymphatic–specific knockouts were generated to examine vessel regeneration in mice.

Results

ERG and FLI-1 protein levels were reduced in the blood and lymphatic vasculature in SSc skin biopsy samples. ERG levels were shown to regulate genes involved in lymphatic vessel specification, including vascular endothelial growth factor receptor 3/FLT-4, lymphatic vessel endothelial hyaluronan receptor 1, SOX-18, and prospero homeobox 1 (PROX-1), whereas FLI-1 enhanced the function of ERG. The ERG–FLT-4 pathway regulated in vitro tubulogenesis in human LECs. Deficiency of ERG or FLI-1 similarly impaired the function of blood vessels in mice. However, only ERG deficiency affected the regeneration of lymphatic vessels during wound healing.

Conclusion

ERG and FLI-1 are essential regulators of blood and lymphatic vessel regeneration. Deficiency of ERG and FLI-1 in SSc endothelial cells may contribute to the impairment of blood and lymphatic vasculature in patients with SSc.

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ERG调节淋巴管规格基因，缺乏ERG会影响伤口愈合相关的淋巴管生成。

目的：据报道，SSc（系统性硬化症，硬皮病）患者皮肤中的血管和淋巴管稀疏。ERG和FLI1是血管生成的重要调节因子，但它们在淋巴管中的作用却鲜为人知。本研究旨在确定ERG和FLI1在出生后淋巴管生成和SSc淋巴系统缺陷中的作用：方法：采用免疫荧光法检测 SSc 和健康对照（HC）皮肤活检组织中的 ERG 和 FLI1。使用芯片对沉默了ERG或FLI1的人真皮淋巴内皮细胞（LECs）进行转录分析。使用 Matrigel 试验检测了 ERG/FLI1 缺乏对人真皮淋巴管内皮细胞体外小管生成的影响。为了研究小鼠的血管再生情况，还产生了ERG和FLI1内皮特异性基因敲除和ERG淋巴特异性基因敲除：结果：在 SSc 皮肤活检组织的血液和淋巴管中，ERG 和 FLI1 蛋白水平降低。研究表明，ERG 可调控参与淋巴管规格化的基因，包括 VEGFR3/FLT4、LYVE-1、SOX18 和 PROX1，而 FLI1 可增强 ERG 的功能。ERG/FLT4通路调控人LECs体外小管生成。缺乏 Erg 或 Fli1 同样会损害小鼠血管的功能。然而，只有 Erg 的缺乏会影响伤口愈合过程中淋巴管的再生：结论：ERG 和 FLI1 是血液和淋巴管再生的重要调节因子。SSc内皮细胞中ERG和FLI1的缺乏可能会导致SSc患者的血液和淋巴管功能受损。

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来源期刊

Arthritis & Rheumatology RHEUMATOLOGY-

CiteScore

20.90

自引率

3.00%

发文量

371

期刊介绍： Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.