Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 580

of ET1 to both ETRA and ETRB on cardiomyocytes activates Gq subunit that
increases intracellular calcium [ 1117 ]. In human myocardium in vitro, endothelin
exerts a positive inotropic effect via sensitization of cardiac myofilaments to calcium
and activation of calcium-sodium exchanger [ 1118 ]. The positive inotropic effect
is associated with a prolongation of the duration of the action potential [ 1119 ], but
endothelins induce coronary vasoconstriction and delayed negative inotropic effects,
which balance and cancel the transient positive inotropic and chronotropic effects.
Endothelin is also a growth factor for cardiomyocytes, inducing muscle-specific
gene transcripts through the possible involvement of protein kinase-C activation or
intracellular Ca 2 + mobilization [ 1120 ].
The endothelin release is shear dependent. The release of ET1 from cultures
of endothelial cells varies with the duration and level of shear [ 1121 ]. Sustained
exposure to low levels of shear (0.18 Pa) or brief exposure ( 1 h) to 1 Pa stimulate

ET1 release via activation of protein kinase-C. Exposure to 0.6 to 2.5 Pa for less than
6 h inhibits ET1 release, implicating either NO and/or cGMP agent. Transient and
long-term steady application of wall shear stress at physiological levels (0.1-3 Pa)
up- and downregulates preproendothelin-1 (ppET1) mRNA, respectively [ 1122 ].
Inhibition of endothelial NO synthase prevents ppET1 mRNA downregulation by
shear stress. Increasing degrees of long-term shear stress upregulate endothelin
receptor-B mRNA via NO and PKC kinase.
Under pathophysiological conditions, ET1 production increases in numerous cell
types, such as endothelial cells, vascular smooth myocytes, cardiomyocytes, and
macrophages (Fig. 9.10 ). Endothelin-1 production is stimulated in various cell types
either under the influence of risk factors (hypercholesterolemia, type-2 diabetes) for
cardiovascular diseases or during development of cardiovascular diseases, such as
atherosclerosis and hypertension.
Endothelin-1 is considered as a developmental factor for vascular dysfunction
that leads to cardiovascular diseases because it causes strong vasoconstriction,
favors inflammation, has proliferative effects, and stimulates free radical produc-
tion and platelet activation [ 1115 ]. Endothelial dysfunction is defined not only by
impaired endothelial function associated with increased production and activity of
vasooconstrictor and pro-inflammatory ET1, but also by reduced availability and
subsequent altered activity of endothelium-derived relaxing factors, such as nitric
oxide, prostacyclin, etc.
High ET1 levels impair endothelial NO production via PKC isoform that leads
to inhibition of NOS3 expression [ 1123 ]. Endothelin-1 stimulates translocation of
PKC

<

α and PKC δ and inhibit that of PKC λ . Endothelin-1 increases cytosolic level

of PKC λ , which is the isoform involved in ET1-mediated NO regulation.

9.10.5 Calcium Signaling in Vasomotor Tone Regulation

Calcium signaling in endothelial cells regulates the function of underlying vas-
cular smooth myocytes. In endothelial cells of resistive arteries such as small