Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 524

PKG1, 89 and PKA; its phosphorylation leads to vasodilation. Phosphorylated VASP
level can serve as an indicator of the NO-sGC-PKG1 pathway that results in
relaxation of smooth myocytes [ 964 ]. Once VASP is phosphorylated by PKA,
VA S P P localizes in endothelial junctional complexes with ZO1, occludin, and
junctional adhesion molecule-1 [ 963 ]. Protein kinase-G phosphorylates P21-
activated kinase, disrupts the NCK-PAK complex, thereby stimulating cell
polarization and preventing angiogenesis, stimulates PAK-VASP binding, changes
PAK localization, and causes remodeling of focal adhesions [ 965 ].

9.6.4.3 Microtubules

Microtubule network is another constituent of the endothelial cytoskeleton that
operates in the barrier between flowing blood and interstitium beneath endothelial
cell monolayer.
Microtubule heterodimers are formed by self-assembly of

α β

-tubulins.
They generate a lattice of rigid hollow rods that span the cytoplasm from the nuclear
region to the cell cortex. The faster growing end (plus-end) that is attached to the cell
cortex is composed of

-and

β

-tubulin that hydrolyzes GTP to GDP, whereas the minus-
end that is fixed to the microtubule-organizing center consists of

α

-tubulin and binds
to GTP without hydrolyzing GTP. Microtubules undergo dynamic instability, as they
permanently shift between lengthening and shortening. Microtubule depolymeriza-
tion increases endothelial permeability.
Microtubules sequester RhoGEFs and LIM kinase and thus control the state
of tubulin and actin polymerization [ 854 ]. Activators RhoGEFs stimulate RhoA
GTPase that disrupts microtubules. Microtubule-coupled nanomotor kinesin can
associate with catenin-

δ

1. Microtubules hence promote intracellular transport of
constituents of adherens junctions. Kinesin-1 is also implicated in component
transfer to focal adhesions, Therefore, microtubules control turnover of endothelial
cell adhesion sites to neighboring cells and extracellular matrix and, consequently,
endothelial permeability.

9.6.4.4 Intermediate Filaments

Intermediate filaments (caliber 10-12 nm, i.e., between that of actin filaments
[ ,25 nm]) participate in cell mechanical in-

tegrity. They are constituted of vimentin and keratin. Vimentin can be phosphor-
ylated by protein kinase-C. Moreover, it can link to cadherin-5 [ 854 ]. Therefore,
intermediate filaments cooperate with the 2 other types of cytoskeleton elements to
modulate endothelial permeability.

∼ 7 nm] and that of microtubules [ ∼

89 cGMP-dependent protein kinase-1 is targeted by atrial natriuretic peptide and nitric oxide.