The broad aim of this project is to test the hypothesis that a decline or loss in vascular function is the proximate cause for certain childhood and adolescent disorders in the testis, such as torsion or inflammation due to orchitis or trauma. We assert that vascular control mechanisms intrinsic to the testis are a significant determinant of Leydig cell (steroidogenesis) and seminiferous tubule (spermatogenesis) performance, because the cell types responsible for these two functions are perfused via separate capillary beds. Each capillary bed is controlled by separate arterioles so the potential for selective perfusion and regulation of cell performance is great. This proposition is supported by a massive body of indirect evidence derived from biochemical, physiological and pathological studies of the testis in healthy and diseased states. The proposed experiments will use the hamster testis as a model because all classes of microvessels can be observed directly by intravital microscopy. Further, the function of the two parenchymal cell types can be assessed independently and simultaneously with quantitative indices of vascular perfusion. To our knowledge, no single laboratory possesses the skills to make simultaneous assessments of testicular cell performance and microvessel function in situ. The special expertise required for these studies has been assembled in this laboratory, and will be used to study the neural, hemodynamic, and cellular mechanisms that limit or control capillary perfusion in the developing testis.
The first aim considers the neural mechanisms controlling arteriolar vasomotor tone and capillary perfusion in the developing testis following the electrical stimulation of the spermatic nerve.
The second aim tests the hemodynamic mechanisms regulating arteriolar vasomotor tone by restricting perfusion pressure and/or flow in the spermatic artery and assessing the capacity of the organ's arterioles to support capillary perfusion.
The third aim addresses the metabolic control or arteriolar tone and capillary perfusion following the respective activation and suppression of Leydig cells.
The fourth aim examines the cellular regulation of capillary perfusion following ischemia/reperfusion injury of the developing testis. Our attention will be focused on the earliest events triggered by ischemic stimuli, including the expression of adhesion molecules that direct the attachment of white blood cells to the luminal surface of venules. Within each specific aim, microvascular control will be assessed concurrently with the performance of testicular cells to test the hypothesized cause-effect relationship between vascular mechanisms that limit or control perfusion and the function of steroidogenic or spermatogenic cells. The results should fill critical gaps in understanding the cellular and molecular basis of microvascular control of testicular performance in normal and ischemic states during development. Insights into these vascular mechanisms can then be exploited to improve the management of certain childhood or adolescent disorders of the testis such as torsion or inflammation.
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