Award Date

1-1-2001

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Science

First Committee Member

George Plopper

Number of Pages

199

Abstract

The development and normal function of cells in the body depend upon interactions with other molecules. One such group of molecules, referred to as the extracellular matrix (ECM), is secreted by subsets of epithelial, endothelial, and mesenchymal cells within multicellular organisms. The laminin families comprise a set of soluble ECM glycoproteins that are required for structural integrity and development in many epithelial tissues. Ln-5 is a laminin isoform composed of three subunits: alpha3, beta3, and gamma2. In this study, I sought to determine temporal and spatial patterns of ln-5 expression in non epithelial tissues. Using an enzyme-linked immunofluorescence amplification system and newly developed photobleaching treatment, I observed ln-5 expression in previously undocumented sites including vascular smooth muscle cells (VSMC) of the aorta, pulmonary arteries, and also in bone and cartilage. In adult animals, VSMC are terminally differentiated and control blood flow and contraction in response to various chemical and mechanical stimuLi However, during the formation of atherosclerotic and restenotic lesions, VSMCs revert to a synthetic a phenotype characterized by a secretory-, proliferative-, and migratory-active state. I analyzed the functional significance of ln-5 expression, which is upregulated by growth factors induced following arterial injury. I found that ln-5 significantly altered the proliferation of VSMC in response to platelet-derived growth factor (PDGF-BB), a potent mitogen and chemoattractant for VSMC. I demonstrated that the alpha6beta1 and the alpha6beta4 integrin complex may be responsible for the initial VSMC adhesion to ln-5. I also demonstrated that ln-5 does not support haptotactic VSMC migration, however PDGF-BB-stimulation greatly enhanced VSMC migration on ln-5. I therefore postulated that PDGF-BB-stimulated MAPK activation is responsible for the increased migratory phenotype of VSMC on ln-5 and found stimulation of VSMC with PDGF-BB reduced VSMC adhesion to ln-5 and concomitantly increased VSMC migration on ln-5 while revealing detectable increases in ERK1/2 activation. As ln-5 is involved in the enhanced migration of various cell types, the increased production and decreased adhesion of VSMC on ln-5 may provide a mechanism for the design of novel and interesting targets in the prevention of pathological processes associated with the arterial vasculature, such as restenosis following angioplasty.

Keywords

Cell; Cell Response; Factors; Growth; Growth Factors; Laminin; Laminin-5; Mediates; Muscle; Response; Smooth; Vascular; Vascular Smooth Muscle

Controlled Subject

Cellular biology; Molecular biology

File Format

pdf

File Size

3932.16 KB

Degree Grantor

University of Nevada, Las Vegas

Language

English

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