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首页> 外文学位 >Mechanisms of action of insulin-like growth factor binding protein-3 in promoting repair in ischemic retinal vascular mouse injury models .
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Mechanisms of action of insulin-like growth factor binding protein-3 in promoting repair in ischemic retinal vascular mouse injury models .

机译：胰岛素样生长因子结合蛋白3促进缺血性视网膜血管损伤模型修复的作用机制。

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摘要

Endothelial progenitor cells (EPCs) are bone-marrow derived cells, which give rise to mature endothelial cells. IGFBP-3 can promote EPC repair and maintenance of blood vessel integrity. This study was conducted to gain insight into IGFBP-3's cellular mechanism of action on EPC-mediated repair in damaged retinal vasculature.;To unveil how IGFBP-3 modulates EPC functional repair, studies were designed to focus on how IGFBP-3 promotes cell migration. For in vivo studies, 2 complementary vascular injury models were utilized: laser occlusion of retinal vessels in adult green fluroscent protein (GFP) chimeric mice and oxygen-induced retinopathy in mouse pups. Intravitreal injection of IGFBP-3 expressing plasmid into lasered adult gfp+ chimeric mouse retinas stimulated homing of EPCs into retinal blood vessels. The gfp+ EPCs also differentiated into various vascular cell types such as pericytes, astrocytes, and endothelial cells. In the OIR model, IGFBP-3 injection prevented cell death of resident vascular endothelial cells, while simultaneously increasing astrocytic ensheathment of retinal blood vessels. For EPCs to orchestrate these cytoprotective and homing effects, they must migrate into ischemic or damaged tissue. Experimental in vitro studies showed their migratory ability is mediated, in part, by endogenous nitric oxide (NO) generation. IGFBP-3 treated EPCs significantly increased NO generation compared to untreated EPCs. IGFBP-3 can signal through the high-density lipoprotein receptor, Scavenger Receptor class B, type 1 (SR-B1), to increase NO production and activity in mature endothelial cells. In EPCs and mature endothelial cells SR-B1 blockade with a neutralizing antibody resulted in a decrease in NO production. Furthermore, when EPCs and mature endothelial cells underwent IGFBP-3 treatment, there was an increase in phospo-endothelial nitric oxide synthase (peNOS) protein expression. IGFBP-3 exposure led to the re-distribution of vasodilator stimulated phosphoprotein (VASP), a NO regulated protein, critical for cell migration of endothelial cells. Lastly, IGFBP-3 effects on vascular permeability were examined. Distinct differences in permeability were found depending on whether the IGFBP-3 was adminstered acutely or there was chronic exposure. IGFBP-3 acutely increased pemeability, while upon longer exposure IGFBP-3 reduced retinal vascular permeability, supportive of its vascular stabilizing ability.;In summay, identification of a new signaling receptor that IGFBP-3 can activate was uncovered. IGFBP-3 can activate the SR-B1 receptor to increase exogenous NO production in EPCs, which leads to increased cell migration of these cells. Due to the positive stimulatory effects of IGFBP-3 on cell migration, it can act as an in vivo homing, resulting in vascular repair and stabilization of injured mouse retinal vasculature. IGFBP-3 has the potential to be used as a therapeutic agent to treat ischemic vascular eye conditions.
机译：内皮祖细胞（EPC）是源自骨髓的细胞，其产生成熟的内皮细胞。 IGFBP-3可促进EPC修复和维持血管完整性。进行这项研究的目的在于深入了解IGFBP-3对受损视网膜血管中EPC介导的修复的细胞作用机制。为了揭示IGFBP-3如何调节EPC功能修复，研究旨在关注IGFBP-3如何促进细胞迁移。在体内研究中，使用了2种互补性血管损伤模型：成年绿色荧光蛋白（GFP）嵌合小鼠的视网膜血管激光阻塞和小鼠幼犬的氧诱导性视网膜病变。玻璃体腔注射IGFBP-3表达质粒到激光成年gfp +嵌合小鼠视网膜中刺激了EPC归巢到视网膜血管中。 gfp + EPC还分化为多种血管细胞类型，例如周细胞，星形胶质细胞和内皮细胞。在OIR模型中，IGFBP-3注射可防止驻留血管内皮细胞的细胞死亡，并同时增加视网膜血管的星形胶质鞘。为了使EPC协调这些细胞保护和归巢作用，它们必须迁移到缺血或受损的组织中。体外实验研究表明，它们的迁移能力部分是由内源性一氧化氮（NO）产生的。与未处理的EPC相比，IGFBP-3处理的EPC显着增加了NO生成。 IGFBP-3可以通过高密度脂蛋白受体B类清道夫受体1型（SR-B1）发出信号，以增加成熟内皮细胞中的NO产生和活性。在EPC和成熟的内皮细胞中，用中和抗体阻断SR-B1导致NO产生减少。此外，当EPC和成熟的内皮细胞接受IGFBP-3处理时，磷酸化内皮一氧化氮合酶（peNOS）蛋白表达增加。 IGFBP-3暴露导致血管舒张剂刺激的磷蛋白（VASP）的重新分布，这是一种NO调节蛋白，对内皮细胞的细胞迁移至关重要。最后，检查了IGFBP-3对血管通透性的影响。根据IGFBP-3是急性给药还是长期暴露，发现通透性存在明显差异。 IGFBP-3急剧增加了通透性，而长时间暴露后，IGFBP-3降低了视网膜血管通透性，支持了其血管稳定能力。总而言之，未发现IGFBP-3可以激活的新信号受体。 IGFBP-3可以激活SR-B1受体以增加EPC中外源NO的产生，从而导致这些细胞的细胞迁移增加。由于IGFBP-3对细胞迁移具有积极的刺激作用，因此它可以作为体内归巢，从而导致受损小鼠视网膜脉管系统的血管修复和稳定。 IGFBP-3有潜力用作治疗缺血性血管性眼病的治疗剂。

著录项

  • 作者

    Kielczewski, Jennifer Lee.;

  • 作者单位

    University of Florida.;

  • 授予单位 University of Florida.;
  • 学科 Health Sciences Ophthalmology.;Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 130 p.
  • 总页数 130
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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