Fibronectin in Cell Growth and Vascular Remodeling

描述（由申请人提供）：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，并且可以导致血管壁的代偿性变化，使壁应力正常化。然而，重塑也可能导致血管壁硬度的改变和血管腔的狭窄，从而损害血管功能。平滑肌细胞迁移和增殖以及细胞外基质蛋白的过量产生和沉积都可以导致血管重塑期间发生的脉管系统变化。我们的数据表明，细胞外基质蛋白，纤连蛋白，在控制细胞外基质蛋白，包括胶原蛋白I的沉积和稳定性中起着关键作用。我们的数据还表明，纤连蛋白聚合到细胞外基质调节粘附依赖性细胞生长，细胞收缩性和细胞迁移。在连续纤连蛋白聚合的情况下，纤连蛋白片段在细胞外基质中积累，表明纤连蛋白聚合部分地通过控制基质蛋白水解来维持细胞外基质结构。因此，调节纤连蛋白聚合的试剂可能在控制细胞增殖、迁移和细胞外基质重塑中是至关重要的，所有这些都是血管重塑的关键组分。在本申请中，我们将测试纤连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生长和迁移的假设，以及纤连蛋白聚合的抑制将减少血管重塑期间平滑肌细胞增生和细胞外基质扩张的程度。为了实现这一点，我们将研究纤连蛋白基质聚合在控制细胞生长，细胞迁移，细胞外基质重塑平滑肌细胞培养在体外，在器官培养中保持的离体动脉，在体内模型血管重塑的作用。这些研究将为平滑肌细胞和细胞外基质之间复杂的相互作用提供重要的见解，这在血管疾病的发展和进展中起着关键作用。

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.