BASIC SCIENCE RESEARCH PROJECTS
Research in the Division of Vascular Surgery is conducted in the Vascular Surgery Research laboratory, at three levels: (patho) physiology, metabolism, and pharmacology. This research involves the study of small (resistance) and large (conduit) arteries. Small arteries are thought to be important for maintenance of peripheral vascular resistance, organ blood flow control and systemic blood pressure regulation. Larger arteries are the predilection sites for disease-specific or iatrogenic events associated with high morbidity and mortality such as aneurysm, atherosclerotic plaque formation and stent-induced restenosis. Research also involves the study of isolated arterial smooth muscle cells. These cells are the target of many antihypertensive drugs which control contraction and relaxation by changing intracellular calcium concentration. The focus of the research with smooth muscle cells is to explore the metabolic pathways which regulate smooth muscle cell calcium homeostasis and to identify new compounds with potential antihypertensive properties.
To study arteries, several systems are used. One is the pressurized arteriograph, a system in which an isolated artery is cannulated, perfused, and kept viable while continuously measuring and adjusting transmural pressure. The studied variable in these experiments is lumen diameter since it is the single most powerful determinant of blood flow. This system is quite powerful and confers the advantage of studying interaction of physical forces (shear stress, flow, transmural pressure) with the vascular wall as well as reactivity to various substances. Another system is the wire myograph. With this system, arteries are stretched between two wires, and tension generated during contraction is measured. This system is connected to a spectrofluorometer which measures the intra-arterial concentration of various signaling molecules. The wire myograph is particularly well suited for the study of cardiovascular drugs but also allows the fine study of metabolic processes activated during arterial contraction and relaxation. Ongoing projects with the wire myograph and pressurized arteriograph involve both the study of animal arteries and arteries isolated from humans. Cell culture techniques and fluorescence methods (fura-2 method for measuring intracellular calcium concentrations, BCECF method for assessing intracellular pH measurements, and calcein for estimation of reactive oxygen species production) are used to study signaling pathways in isolated smooth muscle cells.
The following is a list of current projects:
• Reactivity to homocysteine: Homocysteine, the byproduct of many methyl transferase reactions, is thought to predispose to atherosclerotic disease and hypertension since increased serum homocysteine has been found in many patients with vascular disease. The purpose of this study is to determine the effect of increased concentrations of homocysteine has on vascular reactivity and endothelial cell function. These studies will be performed using both rat mesenteric resistance arteries and human arteries isolated from subcutaneous fat biopsies obtained at the time of surgery.
• Function of hand arteries in Raynaud's phenomenon: Raynaud's phenomenon is a syndrome that is associated with severe vasoconstriction of the arteries of the extremities in response to cold or emotional distress. Since this phenomenon is thought to occur mainly in the digital arteries, studies are underway to assess contractile function of small arteries isolated from human hands of control and Raynaud's patients. This is accomplished through cooperation of the VA Plastic Surgery Service.
• Calcium channels and endogenous alcohols. Voltage-gated calcium channels (L-type) are proteins which regulate calcium influx across the plasma membrane of arterial smooth muscle cells. Previous studies by our group have shown that specific alcohols produced by mammalian cells are potent calcium channel blockers, induce arterial relaxation and lower systemic blood pressure. These observations form the basis of a three-prong research effort involving several O.H.S.U. and V.A. investigators. One focus of this project is to design, synthesize and test, on smooth muscle cells, isolated arteries and in the intact animal, more potent but structurally-related molecules. This research is accomplished through cooperation with investigators at the V.A. Cancer Center and at the O.H.S.U. Heart Research Center (HRC). Another is to characterize the metabolic pathways which control the synthesis and the degradation of these alcohols, and to investigate how ethanol interacts with this metabolism in the cardiovascular and central nervous systems. This research is supported in part by the National Institute of Alcohol Abuse and Alcoholism and is conducted in collaboration with O.H.S.U. and V.A. alcohol investigators. Finally, and more recently, research has begun to evaluate the protective effect of these endogenous alcohols against stent-induced neointima formation and restenosis.
• Fetal programming of adult cardiovascular (CV) diseases. Adult CV diseases are thought to be, in part, programmed during fetal life. The Vascular Surgery Research laboratory, in collaboration with several HRC investigators, is engaged in animal studies which explore the impact of nutrition (diets low in proteins or minerals) and hypoxia during fetal life ("priming") on adult vascular function. This research involves the study of conduit and resistance arteries isolated from "primed" animals (mouse, sheep, microswine) or from primed animals exposed to cardiovascular stress during their adult life.
For more information on any of these projects, please contact: Department of Surgery, Division of Vascular Surgery
Phone: 503-494-7509 Fax: 503-494-4324