The mammalian vascular system is integral to the regulation of homeostasis within an organism. This system is composed of a vast network of blood vessels that transport oxygen and nutrients throughout the body. Blood vessels are lined by endothelial cells (ECs) that provide an interface between circulating blood and the underlying tissue. Based on their unique location, it is unsurprising that ECs are master regulators of numerous physiological processes. ECs are equipped with receptors that interact with their surrounding environment. Among these molecules is Platelet Endothelial Cell Adhesion Molecule-1, or PECAM-1. Since its identification in the early 1990s, PECAM-1 has gained increasing attention for its multi-faceted roles in vascular biology. In this dissertation, I describe two novel roles for PECAM-1 which advance our understanding for how this receptor regulates EC signaling and function.
One of the most important cellular signaling molecules in the vasculature is nitric oxide (NO) generated by the enzyme endothelial nitric oxide synthase (eNOS). NO is required for vasodilation and maintenance of the endothelium. Reduced NO production can lead to endothelial dysfunction, the first step in a host of diseases, including atherosclerosis (hardening of the arteries). Previous studies have suggested a role for PECAM-1 in regulating eNOS activity and NO production. Here, I define a pathway by which PECAM-1 regulates the expression of a trafficking protein that influences eNOS localization and activity.
In the second half of my dissertation, I focus in vivo using wild type and PECAM-1-/- mice. Our lab has shown that PECAM-1-mediated signaling facilitates activation and expression of molecules that participate in cellular crosstalk. Furthermore, it is well documented that cell crosstalk is central to proper cardiac function. Therefore, we hypothesized that genetic deletion of PECAM-1 may have deleterious effects on heart function. In agreement with this hypothesis, we are the first group to report that PECAM-1-/- mice display dilated cardiomyopathy. Work described in this dissertation defines the mechanism leading to these defects in function. Taken together, the work presented in this thesis further expands the evolving roles of PECAM-1 in cardiovascular biology and provides novel insight to its role in regulating organ function.
|Commitee:||Lund, P. Kay, Maeda, Nobuyo, Taylor, Joan, Tzima, Ellie, Willis, Monte|
|School:||The University of North Carolina at Chapel Hill|
|Department:||Cell & Molecular Physiology|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 74/05(E), Dissertation Abstracts International|
|Keywords:||Adhesion molecules, Cardiac function, Cardiovascular homeostasis, Endothelial cells, Nitric oxide synthase|
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