Fibronectin in Cell Growth and Vascular Remodeling

描述(申请人提供)：血管重塑发生在高血压和其他心血管疾病中，包括动脉粥样硬化、再狭窄和静脉移植物狭窄。血管重塑是血管对血流动力学变化或损伤的反应，可导致血管壁的代偿性变化，从而使管壁应力正常化。然而，血管重塑也会导致血管壁僵硬的改变，并使血管管腔变窄，从而损害血管功能。在血管重塑过程中，平滑肌细胞的迁移和增殖，细胞外基质蛋白的过度产生和沉积都会导致血管系统的变化。我们的数据表明，细胞外基质蛋白纤维连接蛋白在控制细胞外基质蛋白的沉积和稳定性方面起着关键作用，包括I型胶原。我们的数据还表明，纤维连接蛋白聚合到细胞外基质中调节黏附依赖性细胞生长、细胞收缩和细胞迁移。在没有持续纤维连接蛋白聚合的情况下，纤维连接蛋白片段积聚在细胞外基质中，这表明纤维连接蛋白聚合维持细胞外基质结构，部分是通过控制基质蛋白分解。因此，调节纤维连接蛋白聚合的药物在控制细胞增殖、迁移和细胞外基质重塑方面可能是至关重要的，所有这些都是血管重塑的关键组成部分。在这一应用中，我们将检验这样的假设，即纤维连接蛋白基质聚合通过改变细胞外基质的组成和稳定性来控制细胞的生长和迁移，以及抑制纤维连接蛋白聚合将减少血管重塑过程中平滑肌细胞增殖和细胞外基质扩张的程度。为了实现这一目标，我们将研究纤维连接蛋白基质聚合在体外培养的平滑肌细胞、器官培养的离体动脉和体内血管重塑模型中控制细胞生长、细胞迁移和细胞外基质重塑中的作用。这些研究将为揭示血管内皮细胞和细胞外基质之间复杂的相互作用提供重要的见解，而细胞外基质在血管疾病的发生发展中起着关键作用。

DESCRIPTION (provided by applicant): Vascular remodeling occurs in hypertension, and in other cardiovascular pathologies, including atherosclerosis, restenosis and vein graft stenosis. Vascular remodeling is a response of blood vessels to hemodynamic changes or injury, and can result in compensatory changes in the vessel wall that normalizes wall stress. However, remodeling can also lead to alterations in vessel wall stiffness, and narrowing of the vessel lumen that compromise vascular function. Smooth muscle cell migration and proliferation, and excess production and deposition of extracellular matrix proteins can all contribute to changes in the vasculature that occur during vascular remodeling. Our data show that the extracellular matrix protein, fibronectin, plays a key role in controlling the deposition and stability of extracellular matrix proteins, including collagen I. Our data also demonstrate that the polymerization of fibronectin into the extracellular matrix regulates adhesion-dependent cell growth, cell contractility and cell migration. In the absence of continual fibronectin polymerization, fibronectin fragments accumulate in the extracellular matrix, suggesting that fibronectin polymerization maintains extracellular matrix architecture, in part, by controlling matrix proteolysis. Hence, agents that regulate fibronectin polymerization are likely to be crucial in controlling cell proliferation, migration, and extracellular matrix remodeling, all of which are key components of vascular remodeling. In this application, we will test the hypotheses that fibronectin matrix polymerization controls cell growth and migration by altering the composition and stability of the extracellular matrix, and that inhibition of fibronectin polymerization will reduce the extent of smooth muscle cell hyperplasia and extracellular matrix expansion during vascular remodeling. To accomplish this, we will examine the role of fibronectin matrix polymerization in controlling cell growth, cell migration, and extracellular matrix remodeling in smooth muscle cells cultured in vitro, in isolated arteries maintained in organ culture, and in an in vivo model of vascular remodeling. These studies will provide important insights into the complex interplay between smooth muscle cells and extracellular matrix, which plays a critical role in the development and progression of vascular disease.