Fenestrae Structure

Morphology and Architecture

Ultrastructural studies have described fenestrae as trans-cellular circular pores with an average diameter of approximately 60 nm (although they can be as large as approximately 125 nm within the liver sinusoidal endothe lium). Fenestrae are encountered in the most attenuated regions of the endothelium, where the cell profile is as little as 40 nm, and span the entire thickness of the cell without disrupting the continuity of the cell membrane (Figure 2). The substances that traverse the pore never encounter the contents of the cytoplasm and are transported in a rapid and presumably energy-efficient manner. This is in contrast to transcytosis, which involves the coupling of energy-rich endocytic and exocytic events. In most vascular beds, the fenestrae contain a diaphragm composed of approximately eight radial fibrils converging in a central knob, which further dissects the pore into 5- to 6-nm openings (Figure 3).

Fenestrae are known to occur in clusters of approximately 50 to 100, termed sieve plates, which are encircled by a microtubule-rich border. Within a sieve plate, fenestrae are found in a near-linear arrangement, with precise spacing between each pore, implying the presence of a complex intracellular scaffolding to support such order. Whether individual fenestrae, or the sieve plates, are stable structures that persist throughout the lifetime of a differentiated cell or dynamic structures that are rapidly turned over, is currently unknown.

Chemical and Molecular Composition

Palade and the Simionescus pioneered the study of fenestrae composition in the 1960s, 1970s, and 1980s by demonstrating that cationized ferritin (CF) preferentially deposited within a glycocalyx visible on the luminal aspect of the fenestral diaphragm. Capitalizing on this initial observation, they used the CF interaction as a probe for the molecular nature of fenestrae, by monitoring its disappearance following treatment with enzymes of defined speci-

Fenestration Endothelial

Figure 1 A scanning electron micrograph from a freeze-fractured glomerulus shows a view down the lumen of a fenestrated capillary. The endothelium appears to have a colander-like structure that permits passage of materials from the blood to the glomerular capsule. (We thank Steve Gschmeissner at Cancer Research UK for this data.) (see color insert)

Figure 1 A scanning electron micrograph from a freeze-fractured glomerulus shows a view down the lumen of a fenestrated capillary. The endothelium appears to have a colander-like structure that permits passage of materials from the blood to the glomerular capsule. (We thank Steve Gschmeissner at Cancer Research UK for this data.) (see color insert)

ficity. Sensitivity to proteases and certain glycosidases as well as affinity for lectins suggested that acidic glycopro-teins and proteoglycans could account for CF-decorated anionic sites on the diaphragms. However, the differential sensitivity to heparinase and heparitinase in the fenestral diaphragms of the intestine and choriocapillaris, respectively, together with variable results in lectin-binding studies in these tissues, highlight organ-specific differences in the glycocalyx composition: heparan sulfate proteoglycans presumably form part of the diaphragms in the intestine, while the closely related molecule heparin is thought to localize on diaphragms of the choriocapillaris. Moreover, binding of CF to fenestral diaphragms is absent altogether in the bone marrow and the fetal liver.

Recent studies by Stan and colleagues identified an endothelial cell-specific protein, Plasmalemmal Vesicle 1 Protein (PV-1) as the first known component of the fenestral diaphragm. PV-1 is a 60-kDa Type II transmembrane glyco-protein that is believed to form homodimers that constitute the primary structural component of the diaphragm. It should be noted that PV-1 and the diaphragm are not unique to fenestrae but also reside within endothelial cell caveolae and transendothelial channels.

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