Microvascular Permeability and Tumor Metastasis - Bioanalysis Advanced Materials Methods and Devices - page 51

walls in disease. Direct and indirect evidence (summarized in [ 57 ]) indicates that
there are tight junction strands with discontinuous leakages and fiber matrix
components (glycocalyx layer) [ 18 ] at the endothelial surface. These structural
components of the microvessel wall form the barrier between the blood stream
and body tissues, which maintains the normal microvessel permeability to water
and solutes. Variations in permeability are caused by the changes in these structural
components.
The molecular basis for the passage of molecules at the level of the breaks in
tight junctions is more likely to be the localized absence of cell-cell contacts
with corresponding loss of a closely regulated molecular sieve as suggested by
Fu et al. [ 28 ] and Michel and Curry [ 57 ]. Thus the junction break-surface matrix
model suggests independent mechanisms to regulate the permeability properties of
the microvessel wall. The junction break size and frequency are likely to involve
regulation of cell-cell attachment via occludin and other junction proteins includ-
ing the cadherin-associated junctions [ 22 ]. On the other hand, the regulation of
glycocalyx density and organization is likely to involve interaction of the molecules
forming the cell surface with the cytoskeleton, and with circulating plasma proteins.
Some of the cellular mechanisms underlying these interactions are reviewed in
[ 22 , 57 ]. Under physiological and pathological conditions, microvessel permeability
can be regulated acutely and chronically by mechanisms that are currently in the
process of being understood.
A serial section electron microscopy study on frog and rat mesenteric capillaries
by Adamson et al. [ 1 ] demonstrated that the junction strand was interrupted by
infrequent breaks that, on average, were 150 nm long, spaced 2-4 m apart

along the strand, and which accounted for up to 10 % of the length of the strand
under control conditions. At these breaks, the space between adjacent endothelial
cells (average ~20 nm) was as wide as that in regions of the cleft between adjacent
cells with no strands. The luminal surfaces of endothelial cells (ECs) lining the
vasculature are coated with a glycocalyx of membrane-bound macromolecules
composed of sulfated proteoglycans, hyaluronic acid, sialic acids, glycoproteins,
and plasma proteins that adhere to this surface matrix [ 64 , 67 , 68 , 78 ]. The thickness
of this endothelial surface glycocalyx (ESG) has been observed to range from less
than 100 nm to 1

m

m for the microvessels in different tissues and species by using
different preparation and observing methods [ 17 , 50 , 33 , 53 , 57 , 72 , 80 , 82 , 87 ].
Although the ESG thickness varies, its density and organization have been reported
to be the same among different tissues and species. The glycocalyx fiber radius is
~6 nm and gap spacing between fibers ~8 nm [ 6 , 72 ].

m

Vesicles . Cytoplasmic vesicular exchange, which behaves like a shuttle bus,
is presumed to be the major pathway for transport of plasma proteins and large
molecules under normal physiological conditions [ 65 ].

Transcellular Pores . In response to local tissue injury or inflammation, additional
transport pathways for large molecules may be opened (transcellular pores) and
existing pathways made less restrictive. The response is complex, and varies
among different animals, organs, and tissues [ 58 ].