Grant: Operating Grant

The small resistance arteries that supply blood to the brain are able to react to changes in blood pressure by changing their diameter to maintain appropriate levels of blood flow under varied physiological conditions. Vessel diameter is altered through the contraction, or relaxation of smooth muscle cells within the vessel wall in response to increased, or decreased blood pressure. Accumulating evidence indicates three major cellular mechanisms control the level of contractile activation of the smooth muscle cells. The big unanswered question is how these mechanisms are activated by increased blood pressure. We will test the hypothesis that specialized surface membrane sites of connection between the extracellular fibres that hold tissues together, and the internal cytoskeleton of the smooth muscle cells, called integrin adhesions, are responsible for converting the mechanical stimulus of blood pressure into a physiological response, in this case, smooth muscle contraction. The molecular basis of the response and the role of integrin adhesions as the mechanotransducer will be studied in normal rats, and in a rat model of type 2 diabetes in which the blood pressure-dependent mechanism for control of smooth muscle contraction is dysfunctional. To accomplish this goal, we will monitor blood vessel diameter and the activation state of key adhesion and contractile proteins in the smooth muscle cells at varied pressures in small segments of arteries kept in short term culture. Understanding the basic mechanisms responsible for this fundamental physiologic mechanism and how alterations in these mechanisms contribute to dysfunction will provide guidance in the development of novel therapies to correct blood flow to the brain. The basic principles identified in this study will have wider implications because an identical dysfunctional control of blood flow is present in other situations, including stroke, Alzheimer disease and aging.