The Regulation of Fibronectin Polymerization on Vascular Inflammation

Extracellular matrix (ECM) remodeling is a cell-mediated process regulated by the complicated interplay between ECM synthesis, deposition and degradation. Many aspects of cell behavior, such as cell growth and migration are influenced by ECM remodeling. ECM proteins can be degraded extracellularly with the production of proteolytic fragments, as well as intracellularly via endocytosis. Accumulation of ECM fragments in vivo has been shown to contribute to the inflammatory processes of diseases. Endocytosis may be a key to limit the accumulation of ECM fragments in the tissues and consequently attenuate the inflammatory reaction. Vascular remodeling occurs during the pathological process of vascular diseases, such as atherosclerosis, hypertension and restenosis. In addition to smooth muscle cell proliferation and migration, ECM remodeling is another characteristic of vascular remodeling. Fibronectin (FN) is one of the principal components of the ECM proteins in the vessel wall. My previous study revealed that inhibition of FN polymerization decreases the expressions of cell adhesion molecules and leukocyte infiltration in the vessel wall, suggesting FN polymerization may play an important role to regulate vascular inflammation in the early stage of injury response. Interestingly, inhibition of FN polymerization has been reported to enhance FN endocytosis and intracellular degradation in lysosomes. Therefore, in this application, we will test the global hypothesis that inhibition of FN polymerization reduces the inflammation in the vascular remodeling process by depleting accumulated FN fragments. The aims to support our hypothesis are: 1) to determine whether inhibition of FN polymerization promotes the depletion of the accumulated FN fragments by increasing FN endocytosis and intracellular degradation in lysosomes; 2) to determine whether inhibition of FN polymerization attenuates the activation of NF-B signaling due to decreased extracellular FN fragments , 3) to determine whether inhibition of FN polymerization decreases leukocytes adhesion and chemotaxis to the vessel wall due to decreased extracellular FN fragments. These results will help us to understand ECM-inflammatory cells interactions and could lead to development of a treatment strategy for pathological vascular diseases in the future.

Project ID:PC9911-0024
External Project ID:NSC99-2320-B182-019-MY2