Selectivity of the Barrier
Attempts to investigate the permeability properties of fenestrae were initiated by Clementi, Palade, Simionescu, and Pino using tracer perfusion studies. Horseradish peroxidase (~4nm in diameter) proved to be readily permeable through diaphragmed fenestrae of the intestinal mucosal capillaries and the ocular choriocapillaris, whereas larger tracers such as ferritin (~11 nm in diameter), or dextrans and glycogens, were variably permeable. These findings fit remarkably well with data developed by Bearer and Orci, who determined that the presence of a diaphragm transected the 60-nm fenestrae into multiple channels of approximately 5 nm in diameter.
Whether permeability through fenestrae is a passive process or is facilitated by specific molecular interactions between components of the pore and traversing substances remains an open question. Although somewhat speculative, future studies in this area may benefit by examining the structure and function of the nuclear pore, a remarkably analogous structure consisting of two lipid bilayers fused to create a seamless circular opening. Transport of molecules between the cytoplasm and the nucleoplasm is chaperoned by proteins of the nuclear pore that first recognize specific export or import signals on potential cargo molecules and then act as shuttling factors in a process regulated by the GTPase, Ran. So far, selectivity within the fenestrae has only been shown with respect to molecular charge, as inferred from studies demonstrating the particularly high affinity of cationic substances for fenestral diaphragms.
Although there is sparse direct evidence of a major physiological role for fenestrae, several functions can be safely attributed to them simply on the basis of their physical properties and their distribution within normal vasculature and during neovascular disease. Fenestrae are postulated to mediate the bidirectional exchange of water, solutes, and small macromolecules between blood and tissues. More specifically, fenestrae are believed to function (1) in the filtration of blood within the choroid plexus that gives rise to cerebrospinal fluid; (2) in the access of endocrine hormones to the bloodstream, such as the release of steroid hormones by the adrenal cortex; (3) in the supply of nutrients to, and removal of waste from, the outer retina by the underlying choriocapillaris; (4) in the ultrafiltration of blood to create primary urine within the kidney glomerulus; and (5) in the filtration of potentially hazardous substances in the blood at the liver sinusoids.
Fenestrae are also observed in normally nonfenestrated vascular beds in association with unwanted angiogenesis and other cardiovascular pathologies. The appearance of fenestrae in the neovasculature of tumors, retinal vessels in diabetic retinopathy, and capillaries of inflamed tissue, such as arthritic joints, coincides with clinical and experimental findings for vascular leakage and edema and implies that fenestrae contribute to the deregulation of vascular permeability. Fenestrae diameter has also been found to alter in conjunction with liver dysfunction, such as cirrhoses, and in kidney disease, such as pre-eclampsia.
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.