Despite tremendous advances in vascular biology, medical imaging, and neurosurgery, cerebral vasospasm remains the leading cause of morbidity and mortality in patients having a subarachnoid hemorrhage who survive to hospitalization. We know that the extravascular blood clot produces a host of potent vasoconstrictors, mitogens, cytokines, reactive oxygen species, and proteases, and that the arterial wall experiences a marked contraction, remodeling, and endothelial damage. Nevertheless, the specific etiology remains unclear and the many different clinical treatments continue to have only limited general success. Given the nearly 40 years of prior research that has focused on in vivo animal models and clinical observations, we submit that there is a need for a new, complementary approach. The purpose of this research, therefore, is to exploit two recent technical advances in our laboratories. Specifically, we propose to study the time-course of changes in cerebral vasospasm due to the separate and combined effects of select molecules using a novel, computer controlled perfusion organ culture system that we recently developed. Moreover, we propose to interpret the associated biomechanical, functional, and cell biological data using a new theoretical framework for arterial growth and remodeling (G&R) that we recently developed. We submit that whereas normal arterial G&R is dominated by mechanotransduction feedback mechanisms that maintain wall shear stress and intramural stresses near preferred/homeostatic values, the over abundance of vasoconstrictors, growth factors, reactive oxygen species, and cytokines released by an evolving clot overwhelm the vessel and induce an aberrant G&R response. We hypothesize that this aberrant response is due primarily to the rapid production of new structurally significant constituents in progressively yasoconstricted configurations, which endows these new constituents with reduced """"""""natural configurations"""""""" but otherwise similar biomechanical properties. In this way, the arterial wall becomes structurally stiffer and less responsive to exogenous vasodilators. We suggest that the sequence of arterial changes are critical in the development of vasospasm and that they can best be delineated in an organ culture system that maintains relevant hemodynamics while allowing the many molecular effectors to be studied both separately and in combination. In summary, we submit that this project will reveal new insight into mechanisms.
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