A study of the role of actin polymerization in the regulation of vascular contractility in a mouse model
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Cardiovascular disease is the leading cause of death in the United States and globally. Aortic stiffness has recently been implicated as an independent risk factor and has attracted research efforts to prevent cardiovascular diseases. More recently, vascular smooth muscle cell stiffness has been proven to play an important role in aortic stiffness, but the precise mechanism of how smooth muscle contributes to vascular stiffness is still unknown. Studying VSMCs (vascular smooth muscle cells) in depth is a hot topic for ongoing research in this decade because, by understanding the mechanisms involved, we can discover novel medications to prevent cardiovascular diseases before they even develop. Given the importance and impact of dVSMCs (differentiated vascular smooth muscle cells) on cardiovascular diseases and the recent movement to the mouse as the preferred animal model, to take advantage of genetically modified mice that can mimic human diseases such as aging, hypertension and atherosclerosis in cardiovascular research, we need in-depth studies of dVSMCs in the mouse. Most studies on vascular smooth muscle have focused on cultured cells while very few have examined contractile dVSMCs. The freshly isolated contractile dVSMC is a better model of vivo cells than are cultured cells. Thus, the purpose of this research was to develop protocols to study the contractility, signal transduction, and cytoskeletal regulation in small mouse blood vessels and contractile cells. Firstly, I developed a novel protocol to freshly isolate dVSMCs from a mouse aorta that are viable and respond to stimulation. This will allow us to better understand signaling pathways controlling dVSMCs and thus to discover targets for application of many therapeutic interventions to prevent cardiovascular diseases. Secondly, I successfully developed a modification of the differential ultracentrifugation protocol on mouse tissue to allow the assay of changes in actin polymerization levels in mouse dVSM. Thirdly, I found for the first time that contractile agonists trigger actin polymerization in mouse VSMCs and postulate that actin polymerization is a regulator of dVSM contractility in the mouse. The current literature strongly suggests that actin polymerization may be a valuable drug target for new cardiovascular therapeutics.