Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 579

class-3 histone deacetylase and its interaction with AMP-activated protein kinase
and endothelial nitric oxide synthase. Phosphorylation of NOS3 by AMPK (Ser633
and Ser1177) primes NOS3 deacetylation induced by Sirt1 to enhance NO produc-
tion [ 1113 ].

9.10.4 Endothelin

Endothelin is a potent vasoconstrictor secreted by endothelial cells. Three
endothelin isoforms (ET1-ET3) have been identified [ 1114 ]. Endothelin-1 is the
single subtype produced in endothelial cells stimulated by ischemia or shear stress.
Endothelin-1 production is also stimulated by thrombin, transforming growth
factor-

, interleukin-1, angiotensin-2, and arginine vasopressin.
Endothelin-1 binds to 2 endothelin receptor types ETRA (ET A1 -ET A2 )and
ETRB (ET B1 -ET B2 ; Vol. 3 - Chap. 7. G-Protein-Coupled Receptors). Receptors
ET A and ET B lodge mainly on vascular smooth myocytes to generate vasocon-
striction and endothelial cells to release NO and prostacyclin, respectively (both
types can be expressed by both cell types). Therefore, the net effect produced by
ET1 is determined on the receptor localization and amount for each cell type,
i.e., the resulting balance between ETRA and ETRB receptors. Endothelin acts
locally. Once endothelin-1 is bound to ETRA of smooth myocytes, it provokes
vasoconstriction. The predominant ETR type in endothelial cells, ET B , is dose- and
PKC-dependently upregulated by wall shear stress, and causes NO release. Under
physiological conditions, ET1 is produced in small amounts, mainly in endothelial
cells, acting as an auto- and paracrine mediator.
Mature ET1 is formed from precursor. Preproendothelin-1 is processed to pro-
hormone big endothelin-1, which is subsequently cleaved by endothelin-converting
enzyme to produce endothelin. Endothelin-1 can be produced by other enzymes
such as chymases, endopeptidases, and other metallopeptidases [ 1115 ].
Locally secreted endothelin-1 binds to its G-protein receptors on smooth
myocytes. This binding leads to the formation of diacylglycerol and inositol
trisphosphate. The latter stimulates Ca 2 + influx from the sarcoplasmic reticulum
and causes vasoconstriction. Endothelin half-life ranges from 15 to 20 mn. There
is no storage. Once released into blood circulation, ET is catabolized as soon as it
reaches the lungs.
Like NO, endothelin has several biological actions. Vascular endothelium
regulates vascular structure. Endothelin yields proliferation of endothelial cells.
ET1 stimulates SMC proliferation. Endothelin thereby regulates extracellular
matrix synthesis by stimulated vascular smooth myocytes. Smooth myocytes
synthesize collagen-1 and -3 in particular. Although angiotensin-2 enhances
collagen-3 synthesis (ET1 does not have significant effect), ET1 increases collagen-
1 production more efficiently than angiotensin-2 in cultured smooth muscle
cells [ 1116 ].
In the heart, endothelin-1 is produced by cardiomyocytes, fibroblasts, and
endothelial cells. Cardiomyocytes predominantly express ET A receptors. Binding

β