Biology Reference
In-Depth Information
trafficking. Caveolae are hypothesized to play a role in both receptor-mediated
and nonreceptor-mediated transcellular transport of macromolecules across the
endothelial barrier (Cohen et al.
2004
). Caveolae were first identified by electron
microscopy as “flask-shaped” invaginations of the plasma membrane. It is these
invaginations that are hypothesized to form the vesicles that mediate transcellular
transport of macromolecules across the endothelium (Komarova and Malik
2010
).
For example, albumin transcytosis is initiated by binding of albumin to the albumin-
binding protein gp60 found in caveolae, resulting in endocytosis and transport of
the caveolae through the endothelial cell (Mehta and Malik
2006
). VVOs, unlike
caveolae, are uncoated interconnected vesicles and vacuoles present in endothelial
cells. VVOs have been shown to be able to participate in transcellular transport of
macromolecules across the endothelium, but their regulation is unknown. Roles
for dynamin, SNARE complexes, actin, and microtubules in the transport of VVOs
through endothelial cells have been suggested (Komarova and Malik
2010
;Mehta
and Malik
2006
). Transcellular transport has been suggested to be regulated in part by
Src kinases, certain PKC isoforms, PI3 kinases, Ca
2+
, and the albumin-binding
protein gp60 (Komarova and Malik
2010
; Mehta and Malik
2006
).
Paracellular transport of macromolecules across the endothelial barrier is achieved
by opening of intercellular gaps between cells. Endothelial cells are connected with
each other by a variety of junctional proteins that form (a) tight, (b) adherent, and
(c) gap junctions. Tight junctions consist of proteins such as claudins, occludin, and
junctional adhesion molecules. These transmembrane proteins have extracellular
domains that bind tightly to each other via homotypic or heterotypic bonds and are
linked intracellularly to the actin cytoskeleton. They are also linked to a variety of
signaling molecules such as PKC-
z
and VASP. Tight and adherent junctions form
zipper-like structures between endothelial cells, while gap junction proteins such as
connexons form transmembrane channels between endothelial cells.
Adherent junctions are comprised primarily by vascular endothelial (VE)-cadherin
whose extracellular domains participate in transoligomeric binding between endo-
thelial cells forming the junction. The cytoplasmic domain of VE-cadherin, like
those of the proteins found in tight junctions, is also proposed to be associated
with the actin cytoskeleton as well as a variety of signaling molecules such as
b
-catenin, RhoGTPases, VASP, casein kinase II, Src kinases, and phosphatases
such as SHP-1.
Both tight and adherent junctions link endothelial cells together forming a
barrier. It is thought that changes in binding of tight and adherent junction proteins
function to regulate the opening and closing of gaps between endothelial cells
allowing paracellular transport of macromolecules.
Gap junctions consist of transmembrane hydrophilic proteins called connexons.
A connexon from each neighboring endothelial cell pair forms an intercellular
pore that can be regulated by serine/threonine and tyrosine phosphorylation. The
pores formed between cells by gap junctions allow for the propagation of trans-
membrane potentials as well as the exchange of signals between endothelial cells
via second messengers such as Ca
2+
and IP
3
(Komarova and Malik
2010
; Mehta and
Malik
2006
).
