DESCRIPTION: The complex signaling mechanisms involved in the regulation of vascular resistance, blood flow and pressure are not well understood. This represents an important problem as these mechanisms are closely associated with a variety of pathological conditions such as hypertension and heart failure. Experimentation has begun to untangle these regulatory mechanisms and continuously provides new insights. There is, however, only limited theoretical development to assist in the elucidation of systems of increased complexity. In this proposal, mathematical models are developed capable of relating macroscopic phenomena such as vessel reactivity, to the underlying biochemical mechanisms. The overall goal is to provide a theoretical framework that will assist in investigations of vascular pathophysiology. The objectivein this particular application is to investigate mechanisms contributing to vascular dysregulation in hypertension. The central hypothesis of this proposal is that altered expression of genes involved in vascular cell electrophysiology and Ca2+ dynamics, leads to abnormal vessel reactivity in disease states. The rationale for the proposed research is that models that can link microvascular phenotype to the underlying biochemical pathways can provide new insights into vascular autoregulation in health and in disease. Once a better understanding of mechanisms that regulate peripheral vascular resistance can be accomplished this will vertically advance our knowledge on the pathology of cardiovascular diseases. Relying on significant prior development of mathematical models, the overall objective of this proposal will be accomplished by pursuing two specific aims: In Aim 1, we will develop multiscale models that will relate macroscale responses in vessel diameter, to the underlying cellular signaling and ion channel activity. We will integrate detailed electrophysiology and Calcium dynamics models for vascular endothelial and smooth muscle cells with biomechanical descriptions into multicellular models of normotensive and hypertensive vessels. In Aim 2, gene expression and vasoreactivity will be evaluated in the hypertensive microcirculation. We will test the hypothesis that disease dependent differences in vessel reactivity correlate to gene expression dysregulation of key cellular components. Candidate genes will be identified and their contribution to hypertensive phenotype will be evaluated by the model in Aim 1. The proposal outlines a new approach to examine vascular function through an integrated theoretical framework that enables us to correlate data from the gene and the cellular level to mascroscopic observations at the vessel level. The proposed research will provide a better understanding of the mechanisms that regulate blood flow and pressure while developing a versatile theoretical framework for pathophysiological investigations.
