Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 570

In endothelial cells, epoxyeicosatrienoic acids activate not only K Ca 1.1 channels,
but also protein kinase-A. They amplify endothelial cell hyperpolarization by
enhancing Ca 2 + influx through TRPC3 and TRPC6, as they also promote their
translocation to the plasma membrane. 158 Epoxyeicosatrienoic acids have not
only intracrine, but also paracrine effects, as they can diffuse to vascular smooth
myocytes.
In endothelial cells, activity of constitutive membrane-bound hemoproteic
members of the cytochrome-P450 superfamily CyP1a1 and CyP1b1 depends on
the pattern of hemodynamic stress [ 1073 ]. 159 Ligand-activated basic helix-loop-
helix transcription factor aryl hydrocarbon receptor (AHR or bHLHe76) increases
CyP1a1 and CyP1b1 transcription. Conversely, CyP1a1 modulates AHR-regulated
genes. 160 Nuclear localization of aryl hydrocarbon receptor that primes CyP1a1
transcription is observed in the descending thoracic aorta, whereas AHR nuclear
localization and CyP1a1 expression is lower in the aortic arch. Steady regime and
pulsatile flow reversal reduce expression of both CyP1a1 and CyP1b1.
During endothelial cell stimulation by hemodynamic stresses, sustained Ca 2 +
influx within endothelial cell cytosol via store-operated channels activated by
Ca 2 + -independent phospholipase-A2 isoform (iPLA2) contributes to release of
vasodilators and stress-induced endothelium-dependent relaxation of adjoining
smooth muscle cells [ 1074 ]. Sustained store-operated Ca 2 + entry can be triggered in
endothelial cells by circulating ATP owing to iPLA2 activation to govern amplitude
and duration of ATP-induced endothelium-dependent vasodilation.
Acetylcholine-induced endothelium-dependent relaxation of smooth myocytes
also depends on iPLA2 activation. Both iPLA2 metabolites, arachidonic acid and
lysophosphatidylcholine, stimulate Ca 2 + entry in endothelial cells. However, only
lysophosphatidylcholine produced by iPLA2 upon Ca 2 + store depletion elicits
store-operated Ca 2 + influx and subsequent NO production to trigger vasodilation
after NO release.

9.10.1.2 Adhesion Molecules

Wall shear stress on the wetted cell surface and pressure-induced axial and
circumferential stretch on the laterobasal plasma membrane are also transduced by

158 Ion channels of the TRPC and TRPV families respond to distinct stimuli as well as different
types of epoxyeicosatrienoic acids. Ion channel TRPV4 is primed by mechanotransduction. It
is also activated by (5,6)- and (8,9)-EET, but not (11,12)-EET molecule. Channel TRPC6 is not
influenced by shear, hypo-osmotic stress, and (5,6)-EET, but is stimulated by (11,12)-EET agent.
159 Enzymes CyP1a1 and CyP1b1 modulate cellular levels of lipid signaling molecules, such as
arachidonic acid and retinoic acid metabolites.
160 Activated aryl hydrocarbon receptor also targets the thrombospondin-1 gene in endothelial cells.
Enzyme CyP1a1 favors thrombospondin-1 expression.