Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 569

NAD(P)H oxidase [ 1062 ]. Stretch-activated Ca 2 + channels are located near inte-
grins. Subunit G

α

q of G proteins participates in flow-induced Ras activation [ 1063 ].
Heparan sulfate, the dominant glycosaminoglycan of the glycocalyx, participates in
mechanosensing for NO synthesis in response to wall shear stress [ 939 ].
Plasmalemmal nanodomains can also be implicated in mechanotransduction.
Caveolae recruit endothelial nitric oxide synthase, cyclooxygenase-2, prostacyclin
synthase, and Src kinase, among other enzymes. Caveolin-1 mediates shear stress
effects by activating extracellular-regulated kinase-1 and -2, but not Jun N-terminal
kinase that, nonetheless, can also be activated by wall shear stress [ 1064 ].
Integrin-cytoskeleton couples act as mechanosensors. Moreover, forces applied
to endothelial cells induce assembly and extension of adhesive structures. Cell adhe-
sion molecules are targeted for transmembrane signaling, using various biochemical
cascades, such as FAK-Src and Rho pathways.
Wall shear stress signals at the endothelial wetted surface via receptor Tyr
kinases [ 1065 , 1066 ], caveolin-1, extracellular signal-regulated kinases [ 1067 ], and
guanine nucleotide-binding (G) proteins [ 805 ].
Wall K + channels shear stress activates mechanosensitive involved in

1 production [ 1068 ], Na + channels implicated in activation of ERK1 and
ERK2 [ 1069 ], and Cl − channels [ 1070 ]. Voltage-gated, inward rectifier K + channels
(K IR 2.1) of endothelial cells respond to shear stress [ 1071 ]. Activity of K IR 2.1 can
also be modulated by protein kinases PKA and PKC, FAK2, and phosphatases. 157
Shear-induced

β

TGF

ionic currents are stopped by channel dephosphorylation by

phosphatase, which thus favors a shear-unresponsive channel state.
Hemodynamic stresses applied by the flowing blood promote endothelium-
dependent vasodilation not only via nitric oxide- and prostacyclin-dependent sig-
naling, but also NO- and PGI2-independent mechanisms.
Hyperpolarization precedes release of vasoactive substances. Endothelium-
derived hyperpolarizing factor (EDHF) is the component of endothelium-dependent
relaxation of smooth myocytes that resists full blockade of nitric oxide synthases
and cyclooxygenases. This mechanism can rely on opening of K Ca 1.1 channels
on vascular smooth muscle and endothelial cells by epoxyeicosatrienoic acids
generated by cytochrome-P450 epoxygenase that leads to Ca 2 + entry and
endothelial hyperpolarization by activating mechanosensitive transient receptor
potential TRPV4 channel. The contribution of epoxyeicosatrienoic acids to flow-
induced vascular response is significant only in arteries that express sufficient
amount of functional TRPV4 channel. Activation of TRPV4 channels by flow
requires not only active cytochrome-P450 epoxygenase, but also translocation of
TRPV4 channel to the plasma membrane [ 1072 ].

157 Protein kinase-A controls the links between K IR 2.1 channel and scaffold A kinase anchoring
protein (AKAP) and SH2 domain-containing SH2D1a adaptor. Kinase FAK2 also associates with
SH2D1a molecule. Scaffold proteins allow formation of proteic complexes with ion channels,
receptors, and enzymes that quickly tranduce signals.