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Type I collagen-integrin interactions in angiogenesis.

机译:血管生成中的I型胶原蛋白-整合素相互作用。

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摘要

Angiogenesis, the formation of new blood vessels by branching from existing vessels, is the primary mechanism for vascular extension in adults. Following injury or hypoxia, endothelial cells proteolytically degrade their basement membranes and encounter an interstitial provisional matrix of diverse composition. Type I collagen, a ubiquitous interstitial extracellular matrix (ECM) molecule and its primary receptor, the alpha2beta1 integrin, are heavily implicated in angiogenesis. We have previously shown that type I collagen gels rapidly induce angiogenesis in human umbilical vein endothelial cell (HUVEC) monolayers in an alpha2beta1 integrin-dependent manner. Analysis of protein content showed that these gels predominantly contained polymerized collagen. Collagen polymerization in contact with the cell monolayer was not required for angiogenesis, and agarose gels failed to induce angiogenesis. The alpha2beta1 integrin has two ligand-binding conformations, intermediate and activated. Integrin clustering further influences ligation and signaling. By immunocytochemistry, alpha2beta1 integrins exhibited a widespread distribution concentrated along cell-cell borders in HUVEC monolayers. Soon after angiogenesis was induced by collagen, alpha2beta1 integrins accumulated on the apical cell surface, aligning with collagen fibers. Activated integrins exhibited a widespread distribution that was not altered by the collagen gel. Antibody-coated beads designed to cluster alpha2beta1 integrins induced tube formation in the absence of collagen; antibodies presented in solution were inactive. Antibody-coated beads targeting alphavbeta3 integrins and PECAM-1 induced tube formation; while anti-alpha1 antibody- or BSA-coated beads did not. A map of functional domains and human mutations on type I collagen suggests the existence of a Cell Interaction Domain that resides in a critical region of the fibril, encompassing the central alpha2beta1 integrin binding site, the vertebrate collagenase cleavage site, and a nearby glycation site. Non-enzymatic glycation of type I collagen has been shown to affect cell interactions. However, a three-dimensional model of integrin-collagen interactions suggests that the nearby glycation site is unlikely to affect collagen-integrin binding directly. Glycation reduced collagen binding for alpha1I, alpha1beta1, and alphavbeta3 integrins in a cell-free system but did not alter the size or the appearance of collagen fibrils. Thus, the Cell Interaction Domain of type I collagen may mediate important aspects of integrin biology including ligation, clustering, and angiogenesis.
机译:血管生成是通过从现有血管分支而形成的新血管,是成年人血管扩张的主要机制。损伤或缺氧后,内皮细胞蛋白水解降解其基底膜,并遇到各种组成的间质临时基质。 I型胶原蛋白是一种普遍存在的间质细胞外基质(ECM)分子,其主要受体alpha2beta1整合素与血管生成密切相关。我们以前已经表明,I型胶原蛋白凝胶以alpha2beta1整合素依赖性方式快速诱导人脐静脉内皮细胞(HUVEC)单层血管生成。蛋白质含量分析表明,这些凝胶主要包含聚合的胶原蛋白。血管生成不需要与细胞单层接触的胶原蛋白聚合,而琼脂糖凝胶则不能诱导血管生成。 alpha2beta1整联蛋白具有两个配体结合构象,中间的和激活的。整联蛋白聚类进一步影响连接和信号转导。通过免疫细胞化学,alpha2beta1整联蛋白表现出广泛分布,沿HUVEC单层细胞边界分布。胶原蛋白诱导血管生成后不久,α2beta1整合素积聚在根尖细胞表面,与胶原蛋白纤维对齐。活化的整联蛋白表现出广泛的分布,其未被胶原凝胶改变。被设计成能使α2β1整合素成簇的抗体包被的珠子在没有胶原的情况下诱导了管的形成;溶液中存在的抗体无活性。靶向αvbeta3整合素和PECAM-1的抗体包被的珠诱导管形成;而抗alpha1抗体或BSA涂层的珠则没有。 I型胶原蛋白上的功能域和人类突变图谱表明,存在于原纤维的关键区域的细胞相互作用域存在,该域包括中央α2β1整联蛋白结合位点,脊椎动物胶原酶裂解位点和附近的糖基化位点。 I型胶原蛋白的非酶糖基化已显示影响细胞相互作用。但是,整联蛋白-胶原蛋白相互作用的三维模型表明,附近的糖基化位点不太可能直接影响胶原蛋白-整联蛋白的结合。糖基化减少了无细胞系统中alpha1I,alpha1beta1和alphavbeta3整联蛋白的胶原蛋白结合,但并未改变胶原蛋白原纤维的大小或外观。因此,I型胶原的细胞相互作用域可以介导整联蛋白生物学的重要方面,包括连接,成簇和血管生成。

著录项

  • 作者

    Turner, Kevin R.;

  • 作者单位

    Thomas Jefferson University.;

  • 授予单位 Thomas Jefferson University.;
  • 学科 Biology Cell.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 186 p.
  • 总页数 186
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 F715.5;
  • 关键词

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