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Mathew et al. Vessel Plus 2020;4:11 I http://dx.doi.org/10.20517/2574-1209.2019.35 Page 7 of 15
[13]
were found to be the major source of CCL5 . Circulating MPs have also been shown to stimulate ICAM
[82]
expression in pulmonary arterial ECs during the late stage in a Sugen + hypoxia model of PH . Increased
+
+
+
levels of platelet-derived MPs, defined as CD31 /CD41 , and endothelium-derived MPs as CD31 /CD41 -
[83]
,were observed in IPAH, HPAH and “associated” PAH compared to controls . Recent studies have shown
+
+
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+
increased levels of circulating MPs of platelet (CD31 /61 ), leukocyte (CD11b ) and endothelial (CD62E )
origin in patients with PH. Furthermore, significantly increased endothelial MP levels were detected in
patients with thrombo-embolic PH compared to non-embolic patients, indicating increased endothelial
[84]
dysfunction in the former . In addition, elevated levels of endothelial MPs, but not leukocyte MPs, prior
+
to treatment are associated with adverse clinical events. Increased CD62e levels are associated with an
[85]
inflammatory state . EVs from animals with PH induce endothelial dysfunction. MPs from hypoxic
rats impair EC-dependent relaxation in pulmonary arteries and aorta via reducing NO production and
[86]
increasing oxidative stress . MPs bearing active tissue factor and CD105 (endoglin) were reported to
be elevated in patients with PAH. Interestingly, in patients with PAH, a further increase in endothelium-
derived CD105 MPs was observed in pulmonary arterial blood compared with venous blood. Furthermore,
patients in functional class III and IV were found to have higher levels of MPs bearing active tissue
[87]
factor . In addition, increased levels of circulating endothelial (CD62E-E-selectin) and CD3 (T cell)-
[88]
derived EVs were observed in patients with different forms of PH . Interestingly, in vitro studies have
revealed that upon exposure to injury, pulmonary arterial ECs release increased amounts of exosomes that
[89]
induce apoptosis-resistant pulmonary arterial SMC proliferation .
Disturbed blood flow has been shown to acutely induce both endothelial activation and apoptosis, resulting
[90]
-
in the release of MPs from activated (CD62E ) and apoptotic (CD31 /CD42b ) ECs . Increased endothelial
+
+
MPs have been reported in adult patients with congenital heart defects (atrial and ventricular septal
defects) especially with ‘associated’ PAH. These endothelial MPs may contribute to inflammation, leading
[91]
to endothelial dysfunction, impaired vasodilatation and inhibit angiogenesis via p39 MAPK . However,
no differences in endothelial MP expression were observed in children with congenital heart defects with
[92]
or without associated PAH .
Apoptotic ECs release exosomes containing tumor susceptibility gene 101 and translationally controlled
tumor protein (TCTP) with antiapoptotic function. Vascular SMCs, upon exposure to these nanovesicles,
exhibit increased resistance to apoptosis and ERK1/2 activation. Silencing TCTP blocks the resistance
[93]
to apoptosis and ERK1/2 activation . TCTP is also a potent mediator of inflammation. In patients with
IPAH, HPAH and in a Sugen + hypoxia model, increased levels of TCTP were found in blood outgrowth
EC. Knockdown of TCTP resulted in increased apoptosis in these cells in in vitro studies. These authors
have further shown increased levels of blood outgrowth EC-derived exosomes and MPs in patients with
PAH associated with BMPR2 mutation [94,95] . Upregulation of miR143-5p has been reported in pulmonary
arterial SMCs from experimental PH and human PAH. Pulmonary arterial SMC-derived exosomes
exhibited enhanced expression of miR143-5p, which induced pro-migratory and pro-angiogenic effects on
[96]
ECs .
CD39, an ectonucleoside triphosphate diphosphohydrolase, is expressed in the lipid raft domain in plasma
membranes of cells including ECs, monocytes and lymphocytes, and functions as an anti-inflammatory
and thromboregulatory factor. The absence of CD39 on ECs results in increased susceptibility of ECs to
[97]
stimulation . Importantly, ECs in IPAH exhibit downregulation of CD39. Furthermore, suppression
of CD39 in in vitro studies results in apoptosis resistant pulmonary arterial ECs, and an increased ATP
[98]
[99]
niche that stimulates SMC proliferation and migration . Visovatti et al. reported the presence of
increased circulating endothelial and platelet MPs with CD39 on the surface in patients with IPAH. In
addition, ATPase and ADPase activities were increased. In PAH, endothelial dysfunction/disruption and/
or apoptosis is the underlying pathological event. Therefore, it is likely that CD39 is lost from ECs, which