Pro-Inflammatory ECM: Key Roles for Hyaluronan and Versican

细胞外基质(ECM)的特定成分在动脉粥样硬化中积聚并促进 血管疾病的炎症期。我们将重点放在其中两个组件上， 透明质酸和凡西嘉，它们相互作用形成更高有序的分子 复合体不仅在血管疾病发展过程中促进细胞外基质的扩张 而且对动脉平滑肌细胞的表型也有显著的影响。最近， 我们发现，富含透明质酸和万西康的ECM促进单核细胞在体内的黏附 透明质酸依赖的方式表明这些特定的ECM成分可能构成 可以被认为是亲炎症的ECM。这些观察结果让我们提出了假设 透明质酸和凡西肯是由血管细胞对特定的炎症反应而产生的 刺激并有助于形成结合单核细胞的细胞外基质。我们进一步假设 单核/巨噬细胞也会合成这些细胞外基质成分，以应对炎症 刺激和降解透明质酸和凡西肯，以及这两种活动之间平衡 部分调节单核/巨噬细胞的表型。为了检验这一假设，我们将 有四个明确的目标。在目标1中，我们将确定这种专门的ECM的全部性质并测试 透明质酸依赖单核细胞对这些成分的需求 粘附力。在目标2中，我们将探讨高脂血症和修饰脂类在 这种细胞外基质的产生，并确定了在发育过程中凡西嘉和透明质酸的变化 动脉粥样硬化。目标3将重点介绍凡西康和透明质酸的合成和降解 单核/巨噬细胞及这些细胞外基质成分对单核/巨噬细胞的影响 增殖、黏附和迁移。在目标4中，我们将测试以透明质酸为基础的 细胞外基质在早期和晚期动脉粥样硬化病变形成中的作用 动脉粥样硬化的易感性和需要特定基因组装的动物 ECM已经被烧毁了。

Specific components of the extracellular matrix (ECM) accumulate in atherosclerosis and promote the inflammatory phase of vascular disease. We have focused on two of these components, hyaluronan and versican, which interact with each other to form higher ordered molecular complexes and not only contribute to ECM expansion during the development of vascular disease but also have a dramatic effect influencing the phenotype of arterial smooth muscle cells. Recently, we found that an ECM enriched in hyaluronan and versican promotes the adhesion of monocytes in a hyaluronan dependent manner suggesting that these specific ECM components may form part of what could be considered a pro-inflammatory ECM. These observations have led us to hypothesize that hyaluronan and versican are produced by vascular cells in response to specific inflammatory stimuli and contribute to the formation of an ECM that binds monocytes. We further hypothesize that monocyte/macrophage also synthesize these ECM components in response to inflammatory stimuli and degrade hyaluronan and versican and that a balance between these two activities partially regulates the phenotype of the monocyte/macrophage. To test this hypothesis, we will have 4 specific Aims. In Aim 1, we will identify the full nature of this specialized ECM and test the requirements for these components for these components in hyaluronan-dependent monocyte adhesion. In Aim 2, we will explore the role that hyperlipidemia and modified lipids play in the generation of this ECM and define the changes in versican and hyaluronan during the development of atherosclerosis. Aim 3 will focus on the synthesis and degradation of versican and hyaluronan by the monocyte/macrophage and the impact of these ECM components monocyte/macrophage proliferation, adhesion and migration. In Aim 4, we will test the importance of this hyaluronan based ECM in the generation of both early and late atherosclerotic lesions by using mouse models of atherosclerosis susceptibility and animals in which specific genes required for the assembly of this ECM have been ablated.