Summary

A newly defined endothelial cell permeability structure, termed the vesiculo-vacuolar organelle (VVO), has been identified in the endothelia of normal venules, in the microvasculature that accompanies tumors, and in venules associated with allergic inflammation. This organelle provides the major route of macromolecular extravasation at sites of increased vascular permeability induced by vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), serotonin, and histamine in animal models. Continuity of these large sessile structures between the vascular lumen and extracellular space has been demonstrated in kinetic studies with ultrastructural electron-dense tracers and by ultrathin serial sections. Ultrastructural enzyme-affinity cytochemical and immunocytochemical studies have identified histamine and VPF/VEGF bound to VVOs in vivo in animal models where these mediators of permeability are released from mast cells and tumor cells, respectively. The high-affinity receptor for VPF/VEGF, VEGFR-2, and platelet endothelial cell adhesion molecule (PECAM-1, CD31) were localized to VVOs and their substructural components by pre-embedding ultrastructural immunonanogold and immunoperoxidase techniques. Similar methods were used to localize caveolin and vesicle-associated membrane protein (VAMP) to VVOs and caveolae, indicating a possible commonality of formation and function of VVOs to caveolae.

Glossary

Caveola: A small, flask-shaped substructural organelle attached to the plasma membranes of endothelial cells. It is distinguished by suborganellar anatomic structures including stomata, knobs, diaphragms, and necks and functions in transendothelial cell transport of macromolecules, either by motion of vesicles through endothelial cells or by fusion of vesicles to form short, transendothelial cell channels.

Enzyme-affinity-gold electron microscopy: A specialized ultrastructural technique developed to identify subcellular sites of specific enzyme substrates by binding of gold-enzyme complexes to sample substrates. An example is the localization of the substrate histamine, by the specific enzyme diamine-oxidase-gold probe.

Vesiculo-vacuolar organelle: A newly identified endothelial cell structure that connects all plasma membrane domains of endothelial cells and provides an anatomical route of transendothelial cell passage of macromolecules. They are particularly prominent in thick venular endothe-lium, and their functions are upregulated by potent permeability mediators.

This organelle is composed of fused small, caveola-sized vesicles and larger vacuoles that display suborganellar anatomic structures including stomata, knobs, diaphragms, and necks.

Acknowledgments

Supported by NIH grants AI-33372 and AI-44066. Portions of this text are reprinted with permission from Dvorak, A. M., and Feng, D. (2001). The vesiculo-vacuolar organelle (VVO): Anew endothelial cell permeability organelle. J. Histochem. Cytochem. 49, 419-431.

Further Reading

1. Kohn, S., Nagy, J. A., Dvorak, H. F., and Dvorak, A. M. (1992). Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels. Lab. Invest. 67, 596-607. This report is the first description of a system of interconnecting vesicles and vacuoles termed vesiculo-vacuolar organelles (VVOs) that are prominent in both tumor-associated and control vessel endothelial cells and provide the primary pathway for macromolecular extravasation. The large increase in permeability characteristic of tumor vessels is likely attributable to upregulation of VVO function.

2. Dvorak, A. M., Kohn, S., Morgan, E. S., Fox, P., Nagy, J. A., and Dvorak, H. F. (1996). The vesiculo-vacuolar organelle (VVO): A distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation. J. Leukoc. Biol. 59, 100-115. This is a report of the high-magnification ultrastructural analysis of electron-dense tracer passage across endothelial cell VVOs. In it the passage of macromolecules was revealed to be regulated at stromatal diaphragms, thereby demonstrating a mechanism for controlling the passage of macromolecules across endothelial cells.

3. Feng, D., Nagy, J. A., Dvorak, H. F., and Dvorak, A. M. (2002). Ultrastructural studies define soluble macromolecular, particulate and cellular transendothelial cell pathways in venules, lymphatic vessels and tumor-associated microvessels in man and animals. Microsc. Res. Tech. 57, 289-326. This review extensively documents what is currently known about the structure and function of VVOs. Studies reviewed here include ultrastructural serial sections and computer-assisted, three-dimensional reconstructions of soluble macromolecular, particulate, and cellular transendothelial cell pathways.

4. Feng, D., Nagy, J. A., Brekken, R. A., Pettersson, A., Manseau, E. J., Pyne, K., Mulligan, R., Thorpe, P. E., Dvorak, H. F., and Dvorak, A.M. (2000). Ultrastructural localization of the vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) receptor-2 (FLK-1, KDR) in normal mouse kidney and in the hyperpermeable vessels induced by VPF/VEGF-expressing tumors and adenoviral vectors. J. Histochem. Cytochem. 48, 545-555.

5. Vasile, E., Qu-Hong, Dvorak, H. F., and Dvorak, A. M. (1999). Caveo-lae and vesiculo-vacuolar organelles in bovine capillary endothelial cells cultured with VPF/VEGF on floating matrigel-collagen gels. J. Histochem. Cytochem. 47, 159-167.

6. Hammel, I., Lagunoff, D., Bauza, M., and Chi, E. (1983). Periodic, multimodal distribution of granule volumes in mast cells. Cell Tissue Res. 228, 51-59.

Capsule Biography

Dr. Dvorak, a pathologist, heads the electron microscopy unit in the Department of Pathology at Beth Israel Deaconess Medical Center, a major teaching hospital at Harvard Medical School in Boston, MA. Her laboratory primarily focuses on the cell biology of endothelial cells, mast cells, basophils, and eosinophils in health and disease. Her work is supported by grants from the NIH.

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