Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 571

adhesion molecules of intercellular and cell-matrix junctions (Fig. 9.8 ). Adhesion
molecules that link endothelial cells either to apposed endothelial cells or basement
membrane transmit sensed mechanical forces and adapt.
Vascular endothelial cell cadherins, platelet-endothelial cell adhesion molecule
PECAM1, and

β 3 integrins are particularly involved [ 1059 ]. The stronger
the changes in hemodynamic stress amplitude and direction, the more sustained
the activation.
The pathways mediated by adhesion molecules use vascular endothelial growth
factor receptor kinase (VEGFR2) that activates phosphatidylinositol 3-kinase, Src
kinase, mitogen-activated protein kinases (ERK, JNK, and P38MAPK), and protein
kinase-B, as well as transcription factors such as NF

α V

B.
Cell adhesion molecules PECAM1 and cadherin-5 on the lateral membrane of
endothelial cells respond to hemodynamic stress. Substance PECAM1 is phosphor-
ylated when endothelial cells are exposed to flow. Phosphorylation of PECAM1
leads to ERK activation [ 1075 ]. Cadherin-5 at adherens junctions complexes with
β

κ

-catenins, PI3K, and VEGFR2 and transmits signals to PKB and B-cell lymphoma
protein BCL2 [ 1076 ]. The interaction of α -catenin with Cdh5-bound β -catenin is

regulated by phosphorylation of stress-modulated β -catenin phosphatase PTPn11

associated with cadherin-5 complexes [ 1077 ].
Integrin- α V β 3

is involved in strain-dependent phosphorylation of VEGFR2 and its binding to SHC
adaptor [ 1066 ], and strain-dependent activation of I

α 5 β 1 enhances stress-dependent cell migration [ 1078 ]. Integrin-

B kinases 161 and NF κ κ B[ 1080 ].

Activation of NF B is mediated by time and magnitude changes in hemodynamic

stress. Small Ras GTPase regulates intracellular transport of inhibitor I

κ

κ B kinase-

α [ 1081 ]. Last but not least, the cytoskeleton transduces force signaling to the

different cell compartments [ 1082 ].

9.10.1.3 Cell Junctions

Cell communications exist between neighboring vascular cells, i.e., between: (1) ap-
posed endothelial cells; (2) adjoining smooth myocytes; and (3) nearby endothelial
and smooth muscle cells through fenestrae of the basement membrane and internal
elastic lamina.
Mechanical stresses imposed on endothelial cells can increase the hydraulic
conductivity of the endothelium. In particular, they act on the paracellular transport
by altering the state of occludins at tight junctions (Sect. 9.6.1 ). After several
minutes of flow exposure, occludin phosphorylation increases [ 940 ]. Stress fiber
bundles in endothelial cells subjected to blood flow develop and align in the
direction of the blood stream. The cytoskeleton fibers associated with tight junctions
between endothelial cells are reinforced and elongated [ 1083 ].

161 Inhibitors of NF

κ κ α β

B(I B ,- ,and- ) sequester in the cytoplasm, hence precluding the binding

of P65 NF (RelA) to DNA and transcription of NF κ B-dependent genes [ 1079 ].

κ B