Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 460

Various mediators, such as thrombin, histamine, hydrogen peroxide, and VEGF,
are able to cause FAK phosphorylation and promote focal adhesions to maintain
endothelial barrier integrity. Furthermore, focal adhesion kinase restores endothelial
barrier function after intervention of inflammatory mediators that causes cell
junction disassembly.
On the other hand, increased FAK activity allows hyperosmolarity-induced
strengthening of adherens junctions. Focal adhesion kinase hinders activity of
GTPase RhoA, as it associates with RhoA inhibitors RhoGAP26 and P190RhoGAP.
Furthermore, focal adhesion kinase activates APAP1 protein. In addition, FAK is
required for normal vascular development.
Kinases of the SRC family can be stimulated by activated integrins. Activated
Src kinase interacts with focal adhesion kinase for full kinase activity. Among
SRC family members, Src kinase contributes to increased endothelial permeability
in response to superoxide anion (O 2 ), thrombin, and VEGF [ 854 ]. 15 Kinase Src
not only elevates endothelial junction permeability, but also caveola-mediated
transcytosis.
Proline-rich Tyr kinase PYK2, a Ca 2 + -dependent cytosolic kinase, also binds
integrins. It is highly expressed in pulmonary endothelial cells. It is rapidly
phosphorylated upon angiotensin and mechanical stimuli. It could regulate endothe-
lial barrier by activating RhoA GTPase. Activated RhoA GTP participates in the
formation of focal adhesions via its effectors RoCK and Diaphanous as well as
PIP5K recruitment.
Transmembrane domains of integrins also interact with tetraspanins, GPI-
anchored urokinase-type plasminogen activator receptor, and caveolin-1. Caveolin-1
is involved in formation of focal adhesions, development of basement membrane,
paracellular endothelial permeability, and integrin signaling [ 854 ].

9.1.2.3 Myoendothelial Junctions

Myoendothelial junctions (MEJ) correspond to endothelial projections that protrude
and cross holes of the endothelial basement membrane and internal elastic lamina
to reach adjacent smooth myocyte membranes.
The principal regulators of vascular tone are neural, endothelial, and mechan-
ical stimuli that initiate vasodilation or vasoconstriction. Three primary vasodila-
tory signals include messengers produced by endothelial cells, nitric oxide and
prostaglandins, and endothelium-dependent vasodilatory hyperpolarization. The lat-
ter refers to the transfer of an endothelium-derived electrochemical current through

15 Inhibition of Src activity by phosphatase PP1 prevents TNF α augmentation of thrombin-
induced endothelial permeability by impeding Ca 2 + entry and internalization of cadherin-catenin
complexes. Moreover, Src phosphorylates MLCK and cortactin, thereby provoking endothelial cell
contraction and increasing endothelium permeability.