Challenges for the Future

The lack of molecular tools, quantitative methods, and suitable model systems have slowed progress on fenestrae research and, to date, the bulk of our knowledge is still largely anecdotal and rich with assumption. A primary challenge for the future is to begin relating definitive functional properties of the fenestrae to the abundant ultrastructural information that has been collected over the past five decades. Recent advances in the fields of genomics and proteomics combined with the development of promising in vitro models for fenestrae formation are expected to open the way for (1) fascinating endothelial cell biology, (2) the potential to create light microscopic and biochemical methods to supplement ultrastructural analyses, and (3) the development of specific antagonists of fenestrae function to elucidate its contribution to cardiovascular function.

Glossary

Caveolae: Flask-shaped invaginations (50 to 100 nm in diameter) at the cell membrane implicated in endocytosis, cholesterol trafficking, and signal transduction. Also known as plasmalemmal vesicles.

Diaphragm: Variable feature of fenestrae and caveolae consisting of radial fibrils converging in a central knob. It is thought to consist of proteins, and its only known component to date is plasmalemmal vesicle 1 (PV-1) protein.

Fenestrae: Transcellular circular pores (60 to 70 nm in diameter) that occur in clusters in attenuated endothelia and are implicated in capillary permeability.

Vascular endothelial growth factor (VEGF): Growth factor expressed as several spliced variants and involved in vasculogenesis, angiogenesis, and vascular permeability.

Further Reading

Bearer, E. L., and Orci, L. (1985). Endothelial fenestral diaphragms: A quick-freeze, deep-etch study. J. Cell. Biol. 100, 418-428.

Braet, F. et al. (1996). Microfilament-disrupting agent latrunculin Ainduces an increased number of fenestrae in rat liver sinusoidal endothelial cells: Comparison with cytochalasin B. Hepatology 24, 627-635.

Clementi, F., and Palade, G. E. (1969). Intestinal capillaries. I. Permeability to peroxidase and ferritin. J. Cell. Biol. 41, 33-58. This article describes one of the earliest attempts to define the permeability proper ties of fenestrae and to distinguish them from those of other endothelial structures. It is selected because the central dogmas postulated are still valid today.

Esser, S. et al. (1998). Vascular endothelial growth factor induces endothelial fenestrations in vitro. J. Cell. Biol. 140, 947-959.

Roberts, W. G., and Palade, G. E. (1995). Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J. Cell. Sci. 108, 2369-2379. This study is selected because it provides the first direct evidence implicating VEGF signaling in fenestrae formation.

Simionescu, N. et al. (1981). Differentiated microdomains on the luminal surface of the capillary endothelium. I. Preferential distribution of anionic sites. II. Partial characterization of their anionic sites. J. Cell. Biol. 90, 605-621.

Simionescu, M. et al. (1982). Differentiated microdomains on the luminal surface of capillary endothelium: Distribution of lectin receptors. J.

Sorensson, J. et al. (2002). Glomerular endothelial fenestrae in vivo are not formed from caveolae. J. Am. Soc. Nephrol. 13, 2639-2647. Stan, R. V. et al. (1999). PV-1 is a component of the fenestral and stomatal diaphragms in fenestrated endothelia. Proc. Natl. Acad. Sci. USA 96, 13202-13207. This article is selected because it describes the identification of the first, and to date the only, known structural component of fenestrae.

Capsule Biography

Ms. Ioannidou, a Ph.D. student registered at University College London, United Kingdom; Dr. Samuelsson, former head of Cell and Molecular Imaging at Procter & Gamble Pharmaceuticals; and Dr. Shima, former head of the Endothelial Cell Biology Laboratory at the London Research Institute, Cancer Research UK, are currently studying various aspects of fenestrae biology at the Eyetech Research Center, Eyetech Pharmaceuticals, Inc.

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