Ceramide signaling and tumor necrosis factor-alpha-induced vasodilation.

Ceramide is a sphingolipid second messenger generated both under basal conditions and via stimulation of a membrane-associated sphingomyelinase. Cytokines such as tumor necrosis factor-alpha (TNF-alpha) have been shown to stimulate ceramide synthesis in non-vascular cell types. TNF-alpha is a cytokine produced from cells of the immune system and of the vasculature in response to tissue injury. TNF-alpha elicits both endothelium-dependent and endothelium-independent vasodilation and is thought to play an important role in regulation of blood flow during inflammatory responses to injury. Therefore, determination of the cellular mechanisms by which TNF-alpha exerts its vascular effects represents a crucial area of research. The goal of this research was to characterize the role of the ceramide signaling pathway as a novel mechanism for mediating the vasodilatory actions of TNF-alpha in the vasculature. The general hypothesis of this dissertation is: Ceramide is a vasodilatory second messenger which mediates the vasodilatory effects of TNF-alpha in the vasculature. This hypothesis was tested by the following specific aims: (1) To determine whether ceramide itself is a vasodilator, (2) to determine whether TNF-alpha stimulates the ceramide signaling pathway in vascular smooth muscle, and (3) to determine the mechanism for ceramide regulation of vascular contractility. The main findings of this dissertation are that: (1) ceramide is an endothelium-dependent and -independent vasodilator, (2) TNF-alpha stimulates ceramide synthesis in vascular smooth muscle, (3) Both TNF-alpha-induced vasodilation and ceramide signaling are dependent upon phospholipase A2 activation, (4) ceramide may elicit vasodilation through inhibition of protein kinase C. The conclusion to be drawn from this dissertation is that TNF-alpha elicits vasodilation through activation of the ceramide signaling pathway. This pathway represents a novel signaling mechanism by which cytokines may induce a vasodilatory response thereby regulating blood flow and pressure.PhDAnimal PhysiologyBiological SciencesCellular biologyHealth and Environmental SciencesPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/131912/2/9938456.pd