Daniel Myers

Date of Award

5-2004

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

Advisor

Lucy Liaw

Second Committee Member

Susan Hunter

Third Committee Member

Thomas Gridley

Abstract

Chronic obstructive vascular disease is a major contributor to mortality in developed nations. The pathology typically involves neointima formation accompanied by vascular remodeling in the presence of inflammation. The disease can be modeled in animals with the response to a direct injury of the vasculature. This text describes a project examining the role of osteopontin (OPN) in vascular remodeling. The projectis goal was to mechanistically describe the contribution of OPN to the vascular injury response. The hypothesis that the presence of OPN affects the formation of neointima and constrictive remodeling associated with vascular injury was addressed using the strategy of comparing the remodeling response induced by carotid artery ligation of wild type mice to mice with a null mutation in the geen encoding OPN at time points known to be critical to lesion development. OPN null mutant mice were compared to wild type mice before and after carotid artery ligation. As substantial variation is observed in the response to carotid artery ligation, the variance was analyzed for potential contributing variables. Distance from the site of ligation was shown to be a significant predictor, and data was analyzed using curvilinear regression. Prior to ligation, OPN null mice had increased heart rate, lower blood pressure, and increased circulating lymphocytes compared to wild type mice. OPN null vessels also demonstrated greater compliance accompanied by a loosely organized collagen network. Following carotid artery ligation, significant differences were also found in the remodeling response of OPN null animals. At 4 days after ligation, leukocyte adhesiodinvasion was diminished by 10-fold in OPN null mice compared to wild type. At 14 days following ligation, the ligated arteries of OPN null mice had smaller neointimal lesions, but greater constrictive remodeling compared to wild type mice, resulting in similar lumen area. Continued remodeling resulted in a similar morphological phenotype in both groups at 28 days. These data show that endogenous OPN regulates normal vascular physiology, and contributes to the vascular remodeling response by regulating vascular compliance and the inflammatory response.

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