Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 458

vasodilator-stimulated phosphoprotein and spectrin, hence linking tight junctions to
the actin cytoskeleton. Therefore, in endothelial cells, adherens and tight junctions
that are intermingled interact via common partners such as ZO1 for their formation,
maintenance, and remodeling. In addition, nectins and their intracellular partners
such as afadin contribute to the organization of adherens and tight junctions.
Endothelial barrier requires endothelial markers cadherin-5 and claudin-5 of
adherens and tight junctions, respectively. Homotypic Cdh5-based adhesions con-
trol claudin-5 expression, as they prevent the nuclear accumulation of transcriptional
repressors FoxO1 and -catenin that inhibit claudin-5 promoter [ 855 ]. 13 This

crosstalk relies on Z01 and JAMs. The crosstalk is mutual as tight junction
molecules such as junctional adhesion molecules can regulate cadherins in endothe-
lial cells.
The RhoA-RoCK pathway that causes actin stress fiber formation can then
induce a loss in junctional occludin, disrupt tight junctions, and increase endothelial
permeability. Histamine, lysophosphatidic acid, thrombin, and vascular endothelial
growth factor disassemble tight junctions via the RhoA-RoCK pathway that
phosphorylates occludin and ZO1, possibly via kinase Src, protein kinase-C, and
casein kinase-2. Conventional PKC isoforms (

β

α , β ,and δ ) also phosphorylate

junctional adhesion molecules.

Gap Junctions

Each gap junction is made up of 2 connexons that correspond to contribution of each
of the 2 partner cells. Connexon is constituted of 6 connexins. The intercellular
pore formed by connexons (caliber 2 nm) has an open or closed configuration.

Gap junction gating is regulated by connexin phosphorylation. Both Ser-Thr and
Tyr phosphorylation of connexins induce channel closure. Phosphorylation also
regulates the rate of gap junction assembly and turnover.
Endothelial cells express connexins Cx37, Cx40, and Cx43. As connexins form
gap junctions, they allow rapid exchange of low-molecular-mass messengers, such
as calcium ions and inositol trisphosphate, between contiguous cells. Junction pro-
tein ZO1 binds connexin-43 and facilitates communication between tight, adherens,
and gap junctions.
Connexins contribute to nitric oxide production and endothelial barrier integrity.
Moreover, endothelial Cx43 can also associate with Cx40 of neutrophils during their
extravasation and vascular smooth myocytes.

∼

13 Cadherin-5 transfers cues either directly by committed signaling effectors, such as phosphatidyl-
inositol 3-kinase or growth factor receptors, or indirectly by tethering and retaining transcription
factors such as β -catenin at the plasma membrane, thereby limiting their translocation to the
nucleus. Cadherin-5 adhesion provokes a sustained activation of the PI3K-PKB pathway that
phosphorylates FoxO1 for cytosolic sequestration, thereby avoiding its interaction with DNA in
cooperation with

β

-catenin and T-cell factor TCF4.