Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 581

( )

ET1 NO

−

−

NOS3

ETRB

peroxynitrate

peroxide

ETRB ETRA

sGC

vasoconstriction (vasodilation)

ET1

Fig. 9.10 Coupling between endothelial and smooth muscle cells in endothelial dysfunction
(Source: [ 1115 ]). In healthy arteries, vasorelaxation is favored because of small ET1 production
and NO activity. In dysfunctional arteries, ET1 synthesis increases in endothelial and smooth mus-
cle cells as well as macrophages. In parallel, ETRB (ET B ) expression in smooth myocytes soars,
hence generating vasoconstriction. Especially in endothelial cells, ET1 can decrease endothelial
nitric oxide synthase (NOS3) expression, thus lowering NO synthesis. Endothelial cells thus
slightly modulate the effects of ET1 in smooth myocytes, moderately reducing vasoconstriction.
Receptor ETRB and predominantly ETRA in smooth myocytes mediate formation of superoxide
(O 2 ). Superoxide forms peroxynitrite (ONOO − ), thereby reducing NO availability. ET1 can
also reduce the expression and activity of endothelial NO synthase. ET1 activates macrophages
and favors their accumulation, thereby causing release of pro-inflammatory and chemotactic
substances, such as tumor-necrosis factor- α and interleukins IL1, IL6, and IL8. These processes
collectively induce vasoconstriction, inflammation, and oxidative stress.

m), localized Ca 2 + sparklets (elementary local
calcium entry) generated by flux through a single transient receptor potential
vanilloid TRPV4 cation channels are amplified by a small number of nearby
TRPV4 channels [ 1124 ]. Local signaling initiated by a sigle TRPV4 channel
leads to a cooperative gating of clustered TRPV4 channels (4-channel cluster)
can yield a robust and rapid communication between apposed cells. The resulting
signal indeed activates intermediate- (IK; K Ca 3.1) and small-conductance (SK;
K Ca 2.3), Ca 2 + -sensitive, K + channels that are boosted by the high Ca 2 + sensitivity
conferred by calmodulin. These K Ca channels are involved in endothelial-derived
hyperpolarization.
Therefore, a small number of active TRPV4 channels (3-8 per cell) mediate
local Ca 2 + cues that, upon cooperative activation of TRPV4 channels in clusters to

mesenteric arteries (caliber ∼ 100