Endoglin Regulates Endothelial Survival and Capillary Tube Stability

内皮糖蛋白调节内皮细胞存活和毛细管稳定性

基本信息

  • 批准号:
    8111481
  • 负责人:
  • 金额:
    $ 8.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-05-20 至 2011-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Specific Aims Transforming growth factor (TGF-2) super family signaling in endothelial cells regulates essential components of angiogenesis and vascular morphogenesis, including proliferation and capillary tube formation. TGF-2 super family ligands exert their regulatory effects through the endothelial cell specific TGF-2 receptor complex, ALK1 (type I receptor) and endoglin (co-receptor), along with the ubiquitous type I TGF-2 receptor, ALK5, to activate the canonical Smad 1/5/8 and Smad 2/3 pathways, respectively. TGF-2 ligands also signal through non-Smad pathways such as MAPKs and PI3K/Akt, although the underlying mechanisms remain obscure. A critical role for endoglin and ALK1 in TGF-2 signaling in endothelial cells is supported by their mutation resulting in the human vascular disease, hereditary hemorrhagic telangiectasia (HHT1 and 2), embryonic lethal phenotype due to defects in angiogenesis when either endoglin or ALK1 is targeted for deletion in mice, and by the elevated expression of endoglin during inflammation and tumor-induced angiogenesis. While important biological roles for endoglin have been established, the molecular basis for endoglin function in vascular biology remains poorly characterized. Here in vitro angiogenesis assays were employed to investigate precisely when and how endoglin regulates endothelial capillary sprouting and tube formation. Comparison of endoglin-null and wild type endothelial cells revealed that endoglin differentially regulates the stability of capillary sprouts and tubes in response to its physiologically relevant high-affinity ligands, TGF-2 and BMP-9. Specifically, TGF-2 resulted in regression of the capillary sprouts and tube structures, primarily through suppression of endoglin-dependent Akt signaling. Conversely, endoglin enhanced Akt signaling in response to BMP-9 to promote capillary stability. These outcomes are attributed to the association between endoglin and the scaffolding/trafficking protein, GIPC, since disrupting their interaction abrogated such endoglin-dependent effects. Given that I recently reported the enhancement of Smad 1/5/8 signaling through GIPC and endoglin, there exists a potential crosstalk between Akt and endoglin-dependent Smad 1/5/8 signaling, which I propose to investigate. Lastly, I discovered a novel interaction between endogenous endoglin and Akt, a finding that will likely yield new facets of endoglin biology. Based upon these preliminary data, I propose the following hypothesis: Endoglin associates with GIPC to promote angiogenesis by stabilizing endothelial capillaries via BMP-9-dependent Akt activation while destabilizing capillaries via TGF-2-dependent suppression of Akt signaling and cell survival mechanisms. This hypothesis will be addressed by the objectives outlined in two specific aims. PUBLIC HEALTH RELEVANCE: A distinctly innovative aspect of my application is in defining a new signaling role for endoglin in altering endothelial cell behavior. The current paradigm describes endoglin as an auxiliary TGF-2 co-receptor that regulates the balance of two opposing signaling pathways, Smad1/5/8 and Smad2/3, which invoke pro- or antiangiogenic responses, respectively [12-22]. However, several lines of evidence challenge this overly simplistic role for endoglin. First, an embryonic lethal phenotype is observed in mice bearing homozygous deletions [1,2]. Second, the significance of endoglin signaling to the Smad pathways during angiogenesis is not fully understood, since these canonical signal transducers can be activated without endoglin expression [25]. My preliminary findings indicate that endoglin engages other important signaling and cellular functions such as regulating Akt activation and downstream cell survival mechanisms. I have so far characterized the ability for endoglin to differentially regulate Akt activation in response to its direct ligands, TGF-2 and BMP-9. A very intriguing aspect my research proposal tries to address, therefore, is how endoglin recognizes two structurally related ligands to elicit such divergent effects on Akt activation. Another innovative aspect of my research proposal involves the plan to use in vitro model systems that incorporate many, if not all, of the separate components of the angiogenic process, such as endothelial cell proliferation, degradation of basement membrane, migration, alignment, and capillary tube formation. Several groups have employed cell proliferation and migration assays to dissect the mechanisms by which endoglin regulates angiogenesis. However, appropriate in vitro systems that comprise most of the sequential stages of angiogenesis would be favorable to monitor the effects of endoglin during angiogenic progression. Manipulating various conditions such as ligand treatment or effects of altering protein levels, would all be possible. I have begun employing such methods to study endoglin function. My preliminary findings based on capillary tube formation assay suggest that endoglin plays an important role in regulating the stability of sprouted capillary tubes, and that this dynamic process is largely governed by Akt signaling and cell survival mechanisms. How endoglin might contribute to the stability of these maturing vessels during angiogenesis is an entirely unexplored area of research, and the basis of my research plan. By employing several new in vitro angiogenesis assays including micro- carrier and co-culturing methods, the proposed work will yield significant insight into when and how endoglin exerts its effects during angiogenesis.
内皮细胞中的转化生长因子(TGF-2)超家族信号调节血管生成和血管形态发生的基本成分,包括增殖和毛细血管形成。TGF-2超家族配体通过内皮细胞特异性TGF-2受体复合物ALK1 (I型受体)和内酰胺(共受体)以及普遍存在的I型TGF-2受体ALK5发挥调节作用,分别激活典型的Smad 1/5/8和Smad 2/3通路。TGF-2配体也通过非smad途径(如MAPKs和PI3K/Akt)发出信号,尽管其潜在机制尚不清楚。内啡肽和ALK1在内皮细胞中TGF-2信号传导中的关键作用被以下因素支持:它们的突变导致人类血管疾病,遗传性出血性毛细血管扩张(HHT1和2),当内啡肽或ALK1在小鼠中被靶向删除时,由于血管生成缺陷导致的胚胎致死表型,以及内啡肽在炎症和肿瘤诱导的血管生成过程中的表达升高。虽然已经确定了内啡肽的重要生物学作用,但内啡肽在血管生物学中的分子基础仍不清楚。本文采用体外血管生成实验来精确地研究内啡肽何时以及如何调节内皮毛细血管的发芽和管的形成。内皮素缺失型和野生型内皮细胞的比较表明,内皮素通过其生理相关的高亲和力配体TGF-2和BMP-9调节毛细血管芽和管的稳定性。具体来说,TGF-2主要通过抑制内啡肽依赖性Akt信号通路导致毛细血管芽和管结构的退化。相反,内啡肽响应BMP-9增强Akt信号,促进毛细血管稳定性。这些结果归因于内啡肽和支架/运输蛋白(GIPC)之间的关联,因为破坏它们的相互作用取消了这种内啡肽依赖的作用。鉴于我最近报道了通过GIPC和内啡肽增强Smad 1/5/8信号,Akt和内啡肽依赖的Smad 1/5/8信号之间存在潜在的串扰,我建议对此进行研究。最后,我发现了内源性内啡肽和Akt之间的一种新的相互作用,这一发现可能会产生内啡肽生物学的新方面。基于这些初步数据,我提出以下假设:内啡肽与GIPC相关,通过bmp -9依赖性Akt激活稳定内皮毛细血管,促进血管生成,同时通过tgf -2依赖性抑制Akt信号传导和细胞存活机制破坏毛细血管稳定。这一假设将由两个具体目标中概述的目标来解决。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Endoglin inhibits ERK-induced c-Myc and cyclin D1 expression to impede endothelial cell proliferation.
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Nam Y Lee其他文献

Context-dependent activation of
上下文相关的激活
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Y. Kim;Piyushi Gupta;Victoria M. Jones;B. Worley;Sara Shimko;D. Shin;LaTaijah C. Crawford;Chi;K. Aird;Thomas Abraham;T. Shepherd;J. Warrick;Nam Y Lee;R. Phaeton;K. Mythreye;N. Hempel;MC R130;Ph.D Mythreye Karthikeyan
  • 通讯作者:
    Ph.D Mythreye Karthikeyan

Nam Y Lee的其他文献

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{{ truncateString('Nam Y Lee', 18)}}的其他基金

TGF-beta signaling in mitochondrial dynamics
线粒体动力学中的 TGF-β 信号传导
  • 批准号:
    10550422
  • 财政年份:
    2023
  • 资助金额:
    $ 8.94万
  • 项目类别:
Tumor-intrinsic and paracrine roles of endoglin in pancreatic cancer
内皮糖蛋白在胰腺癌中的肿瘤内在作用和旁分泌作用
  • 批准号:
    10742322
  • 财政年份:
    2023
  • 资助金额:
    $ 8.94万
  • 项目类别:
Role of spectrin signaling complex in angiogenesis
血影蛋白信号复合物在血管生成中的作用
  • 批准号:
    10301004
  • 财政年份:
    2019
  • 资助金额:
    $ 8.94万
  • 项目类别:
Role of spectrin signaling complex in angiogenesis
血影蛋白信号复合物在血管生成中的作用
  • 批准号:
    10061619
  • 财政年份:
    2019
  • 资助金额:
    $ 8.94万
  • 项目类别:
Mechanism of endoglin-targeted anticancer therapy
内皮糖蛋白靶向抗癌治疗机制
  • 批准号:
    8839215
  • 财政年份:
    2014
  • 资助金额:
    $ 8.94万
  • 项目类别:
Mechanism of endoglin-targeted anticancer therapy
内皮糖蛋白靶向抗癌治疗机制
  • 批准号:
    9245653
  • 财政年份:
    2014
  • 资助金额:
    $ 8.94万
  • 项目类别:
Mechanism of endoglin-targeted anticancer therapy
内皮糖蛋白靶向抗癌治疗机制
  • 批准号:
    9036958
  • 财政年份:
    2014
  • 资助金额:
    $ 8.94万
  • 项目类别:
Endoglin Regulates Endothelial Survival and Capillary Tube Stability
内皮糖蛋白调节内皮细胞存活和毛细管稳定性
  • 批准号:
    8585870
  • 财政年份:
    2010
  • 资助金额:
    $ 8.94万
  • 项目类别:
Endoglin Regulates Endothelial Survival and Capillary Tube Stability
内皮糖蛋白调节内皮细胞存活和毛细管稳定性
  • 批准号:
    8459636
  • 财政年份:
    2010
  • 资助金额:
    $ 8.94万
  • 项目类别:
Endoglin Regulates Endothelial Survival and Capillary Tube Stability
内皮糖蛋白调节内皮细胞存活和毛细管稳定性
  • 批准号:
    8529600
  • 财政年份:
    2010
  • 资助金额:
    $ 8.94万
  • 项目类别:

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