Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 510

9.6.1 Flow-Dependent Transendothelial Transport

Reversible endothelial cell remodeling primed by hemodynamic stresses is

associated with an initial increase followed by a gradual decline ( 40% after

24 h) in electrical impedance of cultured endothelial monolayers. The endothelium
permeability significantly increases after relatively short exposure (1 h) to steady
flow, but markedly decreases (

∼

1/3) after long exposure (7-9 d) [ 938 ]. When
endothelial cell are subjected to sinusoidal flow with an amplitude ratio smaller
than 1, the hydraulic conductivity increases similarly to its response to steady flow.
When the modulation rate exceeds 1, i.e., when flow reversal occurs, the hydraulic
conductivity does not heighten [ 938 ].
Mechanotransduction at the luminal (wetted) endothelial surface provokes nitric
oxide synthesis by nitric oxide synthase. Heparan sulfate, the dominant gly-
cosaminoglycan of the endothelial glycocalyx, participates in mechanosensing that
mediates NO production in response to flow [ 939 ]. Oscillatory flow shear stress
(modulation rate 3/2) provokes a greater production of NO 2 and NO 3 than steady
flow. Hyaluronic acid, another glycosaminoglycan of the endothelial glycocalyx,
enables mechanotransduction, whereas chondroitin sulfate has no effect on shear-
induced NO production and increase in hydraulic conductivity.
In addition, mechanosignaling in response to flow changes in perfused lung
microvessels is initiated in caveolae. Flow-preconditioned cells express a 5-fold
increase in caveolin and other caveolar proteins at the luminal surface with respect
to control (no-flow) condition [ 944 ]. Phosphorylation of luminal surface proteins
(caveolin-1 and nitric oxide synthase NOS3, which are preferentially localized to
caveolae) as well as activation of ERK1 and ERK2 rise upon flow step application
in comparison to no-flow condition, more in flow-preconditioned cells than in the
absence of flow preconditioning.
Under flow reversing conditions, large NO production limits endothelium per-
meability via cAMP formation and cAMP-dependent protein kinase (PKA) that
controls cytoskeletal tension. On the other hand, the hydraulic conductivity rises
under small increases in NO concentration via cGMP production and cGMP-
dependent phophodiesterases and protein kinase (PKG) that targets junctional
proteins such as tight junction occludin.
Mechanotransduction can also exert on the lateral edge of endothelial cells along
the intercellular cleft due to convection generated by the pressure difference across
the endothelium.
Mechanical stress heightens hydraulic conductivity by raising phosphorylated
occludin level and lowering occludin content, hence by tight-junction disassem-
bly [ 940 ]. However, exposure of endothelial cells to sustained equibiaxial cyclic
strains (1 Hz, 24 h) strengthen tight junction, as it elevates amounts of both occludin
and zonula occludens protein ZO1, a linker protein that connects the tight junction
to the actin cytoskeleton, as well as reduces occludin phosphorylation, increases

∼