Inflammation is one of the most important factors in the progression of cardiovascular disease. Thus, it is critical to understand the mechanisms through which leukocyte sequestration and infiltration are regulated during cardiovascular disease. This study aims to study the role of versican-rich extracellular matrix (ECM) generated by vascular smooth muscle cells (SMCs) in promoting leukocyte sequestration and infiltration. Versican is a large chondroitin sulfate proteoglycan highly upregulated during progression of cardiovascular disease. Knocking down versican by antisense or overexpression of versican isoform V3, which lacks glycosaminoglycan binding domains in SMCs, significantly reduces neointima formation and increases elastic fiber formation when these cells were seeded into injured artery in vivo. Elastin-rich ECM negatively regulates monocyte adhesion and migration via activating Src homology 2 domain containing protein tyrosine phosphatase-1 in monocytes. Versican increases hyaluronan associated with cell surface which mediates binding of leukocytes to inflamed SMCs. Versican creates a loose hydrated provisional matrix around cells and also binds to chemokines via its glycosaminoglycan chains, creating a microenvironment which facilitates leukocyte infiltration. Versican promotes metastasis of Lewis lung carcinoma by activating toll-like receptor 2 and stimulating secretion of chemokines such as tumor necrosis factor-alpha and interleukin-6 by myeloid cells. Based on these findings, I hypothesize that versican promotes inflammatory responses by enhancing leukocyte adhesion to the ECM produced by vascular SMCs, upregulating chemotactic migration of leukocytes, and stimulating pro-inflammatory chemokine production by leukocytes during progression of cardiovascular disease. In order to test this hypothesis, I will (1) determine the role of versican in promoting hyaluronan-dependent monocyte adhesion on ECM generated by SMCs, (2) determine whether versican promotes chemotactic migration of monocytes, and (3) determine whether versican promotes pro-inflammatory chemokine production by monocytes.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||07/01/2009 → 06/30/2011|