Grant: Operating Grant

Failure to properly regulate the diameter of small calibre arteries results in hypertension, vasospasm and/or end-organ damage. The molecular basis of the processes that regulate the diameter of small blood vessels is not known with certainty. Small vessels are difficult to study owing to the limited amount of tissue that can be obtained for biochemical analysis of the molecular mechanisms involved. We have developed new methods of greater sensitivity to permit identification of the molecular events controlling arterial diameter. Small arteries react to changes in pressure within the vessel lumen by constricting to pressure elevation and dilating to pressure reduction. This is a fundamentally important mechanism for control of blood pressure, regulating blood flow to the different organs of the body and preventing pressure-induced damage to downstream structures. Changes in arterial diameter are produced by varying the level of contraction of smooth muscle cells within the vessel wall. Previous experiments have focused on the mechanisms that turn the contraction on and off, but our knowledge of the processes that control the magnitude of contraction and, therefore, the extent of change in diameter, is limited. Our recent findings provide evidence for the contribution of a process that enhances the ability of the contractile apparatus of smooth muscle cells to react to pressure. Specifically, they produce more contraction for the same level of stimulation when pressure is increased. The proposed experiments will define the molecular basis of the mechanism by which this process is activated by pressure. Understanding the molecular basis of these mechanisms will define how arterial diameter is regulated in health and provide the foundation for future experiments to identify the dysfunctional mechanisms that contribute to abnormal control of arterial diameter in disease.