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Strassheim et al. Vessel Plus 2018;2:29 I http://dx.doi.org/10.20517/2574-1209.2018.44 Page 11 of 22

by increasing TGF-b1 and CTGF release [226] . The p38a MAPK, activated by Ang-II or non-GPCR stimuli,
such as TGF-b1, or cyclic stretch, has been identified as a master switch, common to many different recep-
tors stimulating fibrosis [198] . The ligand relaxin and its GPCR, RFXP1-4, are Gs-coupled and exert anti-
[227]
hypertrophic and anti-fibrotic effects . In cardiac fibroblasts, PGI -IP-PKA axis activates CREB to inhibit
2
[228]
Ang II-induced SMAD2 activation, attenuating proliferation .
ROLE OF GPCRS IN MONOCYTE/MACROPHAGE WITH RESPECT TO RV FAILURE
Macrophage features in the inflammation associated with heart failure, with resident macrophages being
[191]
described as protective, while recruited being pathogenic . Increasing activity of the transcription factor
KLF4 in resident macrophages to aid their survival or inhibiting MCP-1-CCR2 activity of recruited mono-
[191]
cytes, has been suggested as a potential therapy . Macrophage polarization in PH is thought to contribute
to cardiac and pulmonary inflammation-induced damage and remodeling. M1 macrophage phenotype is
considered pro-inflammatory (versus the M2 phenotype), is involved in resolving inflammation, but im-
plicated in tissue fibrosis [229] . Some studies in PH suggest that M2 macrophages are more damaging than
M1. Antagonizing the CX3CR1 chemokine receptor reduces pathogenic M2 in favor of less damaging M1
phenotype [90,230] . Most chemokine receptors activate Ga /Ga , which have been linked to promotion of
i3
i1
[76]
polarization to M1 macrophage via increased LPS-TLR4-NF-kB, in contrast to CX3CR1 signaling . An
interesting development in macrophage polarization/anti-inflammatory responses are the 6 atypical che-
mokine receptors, ACKR1-6, which are “duds” unable to activate G-proteins, and exert anti-inflammatory
[229]
effects . In particular, the atypical chemokine receptor, CCRL2 (tentatively ACKR5) polarizes in favor of
M2 phenotype [229] . Other GPCRs aiding polarizing to M2 phenotype, include lipoxinA4-activated FPR2,
PGE -receptors, and adenosine A /A -receptors [231-234] . GPCRs clearly critically control macrophage polar-
2B
2A
2
ization and might well be employed to diminish macrophage-induced inflammation occurring in PH. The
role of GPCRs in cardiac inflammation is clearly complex, and it should be mentioned that increasing re-
cruitment of pro-angiogenic monocytes may be beneficial in ED, and is also under control of GPCRs [235-238] .

GPCRS, WHICH MIGHT BECOME CLINICAL TARGETS IN PH
GPCRs activating cAMP-PKA axis in ECs or VSMCs, such as PGI and adenosine (A2 AR), generally
B
2
induce vasodilation, are often anti-inflammatory and protective in PH. Secondly, GPCRs, such as for ape-
lin, PGI2, opioids, which increase NO release from EC to promote vasodilation, are also usually protec-
tive. Thus, any signals increasing cAMP, cGMP, NO and inhibiting Ca are usually protective [178,179] . By
2+
2+
contrast, any GPCR signaling increasing Ca in VSMC, or decreasing NO, cAMP, cGMP, or increasing
inflammation, are usually pathogenic in PH. One very potent anti-inflammatory agent is adenosine, which
exerts powerful anti-inflammatory effects acting at A AR, and clearly plays a protective role in PH [111,239] .
2A
New drugs (such as AEA061) are positive allosteric modulators of A2AAR, that activate receptors without
binding to the normal agonist binding site, offer a therapeutic possibility of fewer side effects as they do
[239]
not act at A , A or A ARs . Activation of A AR without activating A1, A2B, and A3ARs has been an
1
2A
3
2B
issue in developing anti-inflammatory therapies. Other potentially protective GPCRs include FPR2, an
atypical chemokine receptor on macrophages, was reported to exert anti-inflammatory action [229,240] . Other
protective receptors in PH include ET-1 receptor ET B [241] , angiotensin II type 2 receptor [242] , adiponectin-
receptor [36,243] , mas1 (a receptor for angiotensin 1-7) [244] , and relaxin receptors [245,246] . ET receptor is also
B
protective in porto-pulmonary hypertension, a disease secondary to liver failure, but in which the same
therapeutics, PGI -cGMP-PDE-ET-1 receptor antagonist therapies are utilized [247,248] .
2
GPCRs with pathogenic action, which could be antagonized such that the drugs would be protective could
include the CaSR, calcium sensing receptor in EC [12,249] , the succinate GPR91 on cardiac myocytes [205,206] ,
thromboxane receptors [250] , serotonin receptors [251] , LTB receptors [252] , shingosine-1-phosphate recep-
4
tors [13,253-255] amongst others.