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Page 8 of 22 Strassheim et al. Vessel Plus 2018;2:29 I http://dx.doi.org/10.20517/2574-1209.2018.44

like oxidases, NOX1-5 DUOX1, 2 of which are expressed in vascular cells, and their activation involves
Rac1 stimulation by the GEFs, such as engulfment and cell motility protein 1 (ELMO1) [115,117,118] . The super-
oxide generated by NOX enzymes in the extracellular space, is converted to H O , some of which enters
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the cell to stimulate proliferation. H O induces proliferation by changing the balance in protein kinase-
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2
protein phosphatase networks by inhibiting key protein phosphatases via the oxidation of labile sensitive
[119]
cysteine in the active site .
The involvement of HIF-1a in chemokine/GPCR action with respect to PH
HIF-1a and HIF-2a may play a pathophysiological role in PH, and the action of GPCRs overlaps with
that of HIFs [76,120,121] . Firstly, some GPCRs, such as those for estrogen G-protein coupled estrogen recetor-1
(GPER), ET1 (ET ), PGE (EP ), and PGI (IP), can activate HIF-1a even under normoxic conditions [122-131] .
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A
Secondly, ROS increased by GPCRs signaling, inhibit PHD proteins by oxidative inactivation, which in
turn promotes HIF1a activation and its pathological action in PH [132-135] . Thirdly, hypoxic activation of HIF-
1a up regulates G-coupled receptor for SDF-1, CXCR4, implicated in PH by promoting VSMC prolifera-
i
tion [136-139] . Moreover, hypoxia can stimulate ATP release from vasa vasorum endothelial cells (VVEC) by
PI3K-dependent mechanism to promote angiogenesis in an autocrine manner [Figure 2]. This mechanism
implicates purinergic GPCR-dependent activation of HIF-1a and HIF-2a that may amplify hypoxia-
induced vasa vasorum expansion [Figure 3].

INTERACTION OF INFLAMMATORY CYTOKINES AND GROWTH FACTORS WITH GPCRS SIG-
NALING IN PH
PDGF-induced proliferation of VSMC is believed to be a major factor in PH. It is known to be dependent
on Akt activation that can occur in co-operation with some GPCRs, termed trans-activation [140] . Ang II
receptor works in concert with PDGF-receptor tyrosine kinase, promoting Akt-dependent VSMC prolif-
eration [77,141-143] . Thrombin-PAR trans-activates the TGF-b receptor to promote VSMC proteoglycan synthe-
[144]
sis . It is of some interest that PGI has been described as unable to significantly inhibit PDGF-induced
2
[145]
VSMC proliferation, suggesting that other PDGF-neutralizing strategies are needed in PH . MCP-1 and
[146]
IL-6 also work together to induce VSMC proliferation . Activation of inflammatory TXA -TP inhibits
2
FGF-2- or VEGF-stimulated angiogenesis, which could relate to vascular pruning in cardiac and pulmo-
nary vessels, and is an example of GPCR-cytokine interaction [41,147-149] . Protective interactions of GPCRs
with cytokines and growth factors could include the ability of PGI -IP to inhibit the IFNg-induced inflam-
2
[150]
mation, dependent upon induction of suppressor of cytokine signaling 3 (SOCS3) . The GPCR GPR4 ex-
[151]
pressed on ECs, promotes angiogenesis in a Notch-dependent manner . Vessel architecture is maintained
by the ligand-receptor pair jagged expression on EC and Notch expression on VSMC, keeping VSMC in
a differentiated non-proliferating state [152-156] . Both HIF-1a-induced VEGF for reparative angiogenesis and
hypoxia-induced epithelial to mesenchymal transition require Ras family member, RhoE, which activation
[157]
involves SDF-1 GPCR, CXCR4 signaling . RhoE aids in HIF-1a maintenance and is induced by cAMP
[158]
via G -coupled GPCRs . Cardiac angiogenesis is believed to be critically protective in heart disease and
s
[159]
potentially links SDF-1, cAMP, RhoE, HIF-1a, and VEGF into signaling networks .
INTERSECTIONS OF EICOSANOIDS AND GPCRS IN VASCULAR INFLAMMATION
Many eicosanoids induced by vascular inflammation, have short half-lives and must therefore be pro-
duced at the site of action either by monocyte/macrophages, ECs, fibroblasts, cardiac myocytes, or fibro-
blasts [160,161] . Injection of the GPCR-G /G-coupled ligand, PAF into rat lung causes rapid increase in PA
i
q
pressure, linked to LTB production. LTB4-LTB4R, and PAF-PAFR coupled G /G are macrophage acti-
4
q
i
vators and plays a pathological role in PH [162-169] . PGE , an important eicosanoid, which activates several
2
GPCRs, such as G -coupled EP1, G -coupled EP and Ga/Ga -coupled EP . EP promotes PH by increas-
3
3
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13
s
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q
[170]
ing Rho/TGF-b1 signaling . Protective eicosanoids, like PGI , exert anti-inflammatory effects following
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LPS-induced lung injury and PH-induced cardiac inflammation and is active against T cells and macro-