VVO Fate

Once formed, VVOs are sessile, multichambered structures occupying vast expanses of venular cytoplasm. They restrict the passage of macromolecules from the blood vascular spaces at their narrow points in stomata that are closed by thin diaphragms. These diaphragms are opened, making

VVOs porous—a process that is rapidly induced by exposure to well-known permeabilizing molecules, such as VPF/VEGF, histamine, and serotonin.

We envision at least three possible fates for VVOs in venular endothelium: (1) opened, leaky VVOs could close, thereby returning vessels to their prior nonleaky state; (2) opened, enlarged stomata in permeabilized VVOs could open further, allowing retention of opened vesicles and vacuoles in their fused state to form large transcel-lular holes through which circulating endogenous and exogenous particulates could freely enter the extravascular space [3]; or (3) VVOs could serve as an extensive intracel-lular store of membranes that, in certain circumstances, could rapidly and greatly expand the endothelial plasma membrane. This expansion could be instrumental in the rapid formation of large vessels ("mother" vessels) in VPF/VEGF angiogenesis models [4] and in the enhanced endothelial surface process and migration sac formation that accompanies endothelial thinning and loss of VVOs at points of neutrophil transmigration in an animal model of acute inflammation [3].

Presently, there are no data to confirm the first possibility, but long-term studies of VVO architecture following transient permeability events are in progress. Considerable data have accrued in support of the second proposed fate of VVOs [3]. In studies of VPF/VEGF and other vasoactive mediators in combination with soluble macromolecular tracers, we encountered relatively few openings across venular endothelium. In such experiments, ferritin and HRP extravasated across venular endothelium primarily by way of VVOs. However, when we used colloidal carbon (d ~ 50 nm) as a tracer, a particulate that is, for the most part, too large to enter or pass through the narrow necks of stomata in VVOs, we observed a substantial (threefold to thirtyfold) increase in endothelial cell openings [3], suggesting that, in response to vasoactive mediators, holes may develop from a rearrangement of VVO vesicles and vacuoles to form larger membrane-lined vacuolar structures and, eventually, channels of sufficient size to allow the passage of particulate tracers as large as erythrocytes.

The third possible fate of VVOs as a membrane store for rapidly expanding endothelial plasma membrane has gained some support from studies of transendothelial cell neutrophil migration in acute inflammation [3]. Here, we noted that VVOs became less numerous in thinned endothelium through which neutrophils were traveling, and that a markedly expanded endothelial cell luminal membrane covered many extended endothelial cell cytoplasmic processes and provided additional membrane to form migration sacs that enclosed migrating neutrophils. By analogy, the markedly and rapidly enlarged "mother" vessels in tumor and VPF/VEGF-induced angiogenesis models lend support to the third possibility, since VVOs were not a conspicuous component of the cytoplasm of the enlarged mother vessels and the formation of mother vessels occurred rapidly in an angiogenesis model. VVOs may provide membrane for the rapid formation of these vessels in angiogenesis.

Thus, the fate of VVOs includes at least three possibilities—to recover in place by reforming diaphragms between their components or to persist by remaining in place without reclosure of stomata (e.g., in acute and chronic inflammation); to expand further to form large transcellular holes (to facilitate transcellular trafficking in inflammation); or to provide rapid expansion of endothelial plasma membranes by externalizing their membrane in acute inflammatory and angiogenesis models.

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Essentials of Human Physiology

Essentials of Human Physiology

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