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Page 6 of 22 Strassheim et al. Vessel Plus 2018;2:29 I http://dx.doi.org/10.20517/2574-1209.2018.44
tion yet tested, the combination could be more effective for patients’ survival than any monotherapy [2,80,81] .
Statins may work in PH models by inhibition of isoprenoid intermediates, farnesyl pyrophosphate and
geranyl-geranyl pyrophosphate, essential for the post-translational isoprenylation, membrane localization,
and activation of Ras and Rho small GTP-binding protein families, respectively, thus inhibiting RhoA-
[82]
ROCK .
Post-receptor mechanisms leading to decreased vasodilator GPCR responses
Post-receptor mechanisms also operate to limit vasodilator response in PH, such as the several hits to the
critical NO-cGMP-PKG vasodilation system. Firstly, inflammatory cytokines down regulate eNOS and up-
regulate reactive oxygen species (ROS), including superoxide [83-85] . Secondly, due to peroxynitrite formation,
[86]
NO level is depleted . Thirdly, vasodilator response can be limited due to increased PDE5 expression [87,88] .
A
Up regulation of both cAMP-PDEs, and cGMP-PDE is an important pathological event, which decreases
[89]
effectiveness of vasodilator GPCRs and needs further investigation . The PDEs are a complex family of
enzymes with 21 genes, and 11 subfamilies, and some share little sequence identity . Due to a combina-
[31]
tion of post-receptor mechanisms, increased expression of cAMP- and cGMP-PDEs, inhibition of eNOS
activity, and decreased NO availability (as a result of ROS production), the effects of vasodilators in PH are
diminished.

HOW GPCRS FUNCTION IN VASCULAR INFLAMMATION-DRIVEN REMODELING
GPCRs induce cytokine/chemokine production from leukocytes, VSMC, ECs, fibroblasts, and cardiac
myocytes and are pathogenic in PH. Up regulation of SDF-1 in activated T cell results to the expression
and secretion of RANTES and Monocyte Chemo-attractant protein 1 (MCP-1). These chemokines promote
proliferation of VSMC, matrix remodeling, and ROS production [90-92] . Additionally, GPCRs like serotonin
receptor and purinergic P Y R, promote migration of bone marrow derived blood cells, essential to the de-
2 14
velopment of PH [93,94] .

DAMAGE MOLECULAR PATTERNS AS A POTENTIAL CONTRIBUTOR TO VASCULAR INFLAM-
MATION IN PH
The driving forces behind vascular inflammation in PH are unclear, but it is likely that sterile inflam-
mation-damage molecular pattern (DAMP) systems play a role. Purinergic receptors are also critical in
DAMP responses. ATP, ADP, or adenosine are released from extracellular stimuli-activated, hypoxic, or
damaged cells and play prominent roles in inflammatory and secretory responses associated with tissue
repair. Of the 19 purinergic receptors, 12 are GPCRs nucleotide P2YR 1, 2, 4, 6, 11-14 and adenosine A , A , A
2A
2B
1
A , and the remaining 7 purinergic receptors P2X , are ligand gated cation channels [95-100] . Macrophage
3
1-7
activation in PH is potentiated by the P Y [101-103] . Some data suggest antagonizing the ATP-activated P X
2 6
2 1
[104]
purinergic receptor could be beneficial in PH . Both P Y and P Y purinergic receptors have been shown
2 1
2 12
to be partially responsible for PA pressure increase due to hypoxia . Hypoxia-induced ATP release from
[105]
PA adventitial fibroblasts and vasa vasorum endothelial cells (VVEC) induces mitogenic and angiogenic
responses in VVEC in autocrine/paracrine manner [95,96,106] [Figure 2]. Released ATP and ADP are degraded
rapidly to adenosine. Activation of the A adenosine receptor has been reported to be protective against
2A
PH, but the activation of A -AR results in pathogenic effects [107-112] . The involvement of DAMPS-GPCRs in
2B
PH is understudied, and therapeutic possibilities remain to be explored.
PATHOGENIC CHEMOKINE GPCRS
Small G-proteins in chemokine receptor-stimulated VSMC proliferation
In VSMC, MCP-1 acting via G-coupled CCR2, stimulates G-dependent proliferation, that also involves ac-
i
i
[113]
tivation of the small G proteins . One of the mechanisms includes p115RhoGEF-dependent activation of