Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 476

9.5.2 Nuclear Receptors

Drug catabolism ensures the body's protection against toxics. The nuclear receptor
NR1i2 30 controls drug clearance via transcription of genes involved in drug
transport (multidrug resistance transporter MDR1) and metabolism (conjugation
[glutathione transferase] and oxidation [cytochrome-P450 CyP2b, CyP2c, and
CyP3a, and glutathione peroxidase]). In human vascular endothelial and smooth
muscle cells, activated NR1i2 stimulates expression of the Mdr1, CYP3A, CYP2B,
and CYP2C genes as well as increases cellular level of glutathione and activity
of glutathione peroxidase to protect the vasculature, in particular against oxidative
stress [ 879 ].

9.5.3 Examples of Endothelial Receptors

9.5.3.1 Endothelial Protein-C Coreceptor

Endothelial cells express endothelial protein-C receptor (EPCR) to regulate the
protein-C anticoagulant and anti-inflammatory pathway via the thrombin-thrombo
modulin complex. Cytoprotective activated protein-C can also upregulate anti-
apoptotic and anti-inflammatory gene expression.
Vascular smooth myocytes also express EPCR [ 880 ]. In smooth myocytes, ac-
tivated protein-C induces phosphorylation of extracellular signal-regulated kinases
ERK1 and ERK2 via peptidase-activated PAR 1 receptor. Effect of activated protein-
C is significantly enhanced in the presence of thrombin.
However, thrombin does not engage EPCR coreceptor; it cleaves completely
PA R 1 that is subsequently internalized and degraded [ 881 ]. Thrombin binds to PAR 1
and activates preferentially subunits of the Gq and G12/13 subclasses of G protein
heterotrimer to initiate Ca 2 + mobilization and PKC activation on the one hand and
to disrupt the endothelial barrier using monomeric RhoA GTase, on the other.
On the other hand, activated protein-C connects to EPCR and causes a limited
cleavage of PAR 1 receptor [ 881 ]. Moreover, activated protein-C and thrombin stim-
ulate Rac1 and RhoA GTPases using G protein and -arrestin, respectively [ 882 ].

Therefore, activated protein-C operates as a biased agonist that activate

β

β -arrestin

signaling. 31

Activated protein-C releases β -arrestin-2 from PAR 1 , which then

30 A.k.a. pregnane X receptor (PXR) and steroid and xenobiotic receptor.
31 Biased agonists activate β -arrestin signaling. Ubiquitous adaptors β -arrestin-1 and -2 desensitize
G-protein-coupled receptors, thereby blocking G-protein signaling as well as supporting receptor
endocytosis, thus mediating G-protein-independent signaling. On the other hand, ubiquitinated

β

-

arrestin-2 that acts as a ubiquitin ligase adaptor, stabilizes GPCR signalosomes.