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:
    8459636
  • 负责人:
  • 金额:
    $ 24.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-07-01 至 2014-11-30
  • 项目状态:
    已结题

项目摘要

Specific Aims Transforming growth factor (TGF-¿) superfamily signaling in endothelial cells regulates essential components of angiogenesis and vascular morphogenesis, including proliferation and capillary tube formation. TGF-¿ superfamily ligands exert their regulatory effects through the endothelial cell specific TGF-¿ receptor complex, ALK1 (type I receptor) and endoglin (co-receptor), along with the ubiquitous type I TGF-¿ receptor, ALK5, to activate the canonical Smad 1/5/8 and Smad 2/3 pathways, respectively. TGF-¿ 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-¿ 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-¿ and BMP-9. Specifically, TGF-¿ 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-¿-dependent suppression of Akt signaling and cell survival mechanisms. This hypothesis will be addressed by the objectives outlined in two specific aims.
具体目标 内皮细胞中的转化生长因子(TGF-β)超家族信号调节 血管生成和血管形态发生的重要组成部分,包括 增殖和毛细血管形成。TGF-β超家族配体发挥其 通过内皮细胞特异性TGF-β受体复合物ALK 1的调节作用 (type I受体)和内皮糖蛋白(辅助受体),以及沿着无处不在的I型TGF-γ 受体,ALK 5,激活经典的Smad 1/5/8和Smad 2/3途径, 分别TGF-β配体也通过非Smad途径如MAPKs发出信号 和PI 3 K/Akt,尽管潜在的机制仍不清楚。的关键作用 内皮糖蛋白和ALK 1在内皮细胞TGF-β信号传导中的作用得到了它们突变的支持 导致人类血管疾病,遗传性出血性毛细血管扩张症(HHT 1 和2),胚胎致死表型,由于血管生成缺陷时,内皮糖蛋白 或ALK 1在小鼠中靶向缺失,并且通过内皮糖蛋白的表达升高, 在炎症和肿瘤诱导的血管生成过程中。虽然重要的生物学作用 内皮糖蛋白在血管内皮功能中的分子基础已经建立, 生物学的特征仍然不明确。在这里,采用体外血管生成测定法, 研究内皮糖蛋白何时以及如何调节内皮毛细血管出芽 和管形成。内皮素缺失型和野生型内皮细胞的比较显示, 内皮糖蛋白差异调节毛细血管芽和管的稳定性, 与其生理相关的高亲和力配体TGF-β和BMP-9的反应。 具体来说,TGF-β导致毛细血管芽和管结构的退化, 主要通过抑制内皮素依赖性Akt信号传导。相反,内皮糖蛋白 增强响应BMP-9的Akt信号传导以促进毛细血管稳定性。这些 结果归因于内皮糖蛋白与 支架/运输蛋白,GIPC,因为破坏它们的相互作用, endoglin依赖的作用。鉴于我最近报告了Smad的增强 通过GIPC和内皮糖蛋白的1/5/8信号传导,在GIPC和内皮糖蛋白之间存在潜在的串扰。 Akt和内皮素依赖的Smad 1/5/8信号,我建议调查。 最后,我发现了内源性endoglin和Akt之间的一种新的相互作用, 这可能会产生内皮蛋白生物学的新方面。根据这些初步数据,我 我提出了以下假设:内皮糖蛋白与GIPC相关, 通过BMP-9依赖性Akt激活稳定内皮毛细血管的血管生成 而通过TGF-β依赖性抑制Akt信号传导和细胞凋亡, 生存机制。这一假设将通过目标来解决 有两个具体目标。

项目成果

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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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    8111481
  • 财政年份:
    2011
  • 资助金额:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 项目类别:

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