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Mathew et al. Vessel Plus 2020;4:11 I http://dx.doi.org/10.20517/2574-1209.2019.35 Page 5 of 15

Figure 2. MPs are formed by the plasma membrane pinching off and encapsulating cytosolic components. MPs: microparticles

[47]
MPs play an important role in inflammation, EC function and cellular survival . Circulating MPs impair
the atheroprotective function of ECs, in part, by decreasing NO synthesis. Increased levels of circulating
MPs are useful biomarkers of vascular injury and a predictor of adverse cardiovascular events and mortality
in patients with atherosclerotic disease. Atherosclerotic lesions contain a large number of MPs of leukocyte,
[48]
SMC, EC and red blood cell origin , and even patients with subclinical atherosclerosis exhibit increased
[49]
levels of circulating leukocyte-derived MPs .
In addition, MPs promote coagulation, inflammation and alter angiogenesis and apoptosis in ECs.
Studies indicate that MPs induce EC dysfunction by disrupting NO release. Endogenous NO inhibits
the release of endothelial MPs upon stimulation with C-reactive protein through a tetrahydrobiopterin-
[50]
dependent mechanism . Endothelial MPs deliver C-reactive protein and participate in inflammation and
[51]
coagulation . MPs from T- lymphocytes depress endothelial nitric oxide synthase (eNOS) activity and
increase oxidative stress in ECs; however, T-lymphocytes carrying morphogen sonic hedgehog increase
[46]
NO production . Furthermore, the release of MPs carrying lytic complement C5b-9 complex protects
ECs from complement-induced lysis. MPs from leukocytes stimulate pro-inflammatory genes in ECs
in vitro, resulting in the release of cytokines and leukocyte-EC adhesion molecules. On the other hand,
MPs from polymorphonuclear leukocytes contain annexin-1, a functionally active anti-inflammatory
[52]
protein. In vivo, annexin-1 inhibits the interaction between leukocytes and ECs . In in vitro studies,
the inhibition of endothelial MP release has been shown to induce caspase-3 accumulation, leading to
[53]
cellular apoptosis. Thus, endothelial MP release could protect EC apoptosis by reducing caspase-3 levels .
Pulmonary microvascular ECs have higher levels of basal cAMP and pulmonary ECs release cAMP
containing EVs. These EVs are thought to facilitate compartmentalized cAMP signals and thus, may
[54]
strengthen the endothelial barrier . In vitro studies have shown that MPs derived from platelets stimulate
cell proliferation, migration, and tube formation in ECs. In addition, metalloproteinases contained in
endothelial MPs regulate proteolytic activity on the matrix and elicit angiogenesis. Furthermore, MPs
[55]
derived from endothelial progenitor cells may induce apoptosis-resistant cell proliferation . MPs contain
the cell surface protein and cyotoplasmic components of the original cell, and exhibit phosphatidylserine
on the surface that accounts for their procoagulant character. MPs from T cells induce EC dysfunction by
altering NO and prostacyclin pathways. T-lymphocyte-derived MPs reduce eNOS expression and vascular
[56]
relaxation, and exhibit increased expression of caveolin-1 .
EVs participate in physiological as well as pathological conditions depending on their cargo. EV biogenesis
is dysregulated in pathological conditions. Release of EVs can induce inflammation, angiogenesis and
thrombosis, and are implicated in many diseases such as cancer, chronic obstructive pulmonary disease,
atherosclerosis and PH. During degranulation, activated polymorphonuclear leukocyte-derived exosomes
+
+
(CD63 /CD66b ) acquire surface-bound neutrophil elastase that is resistant to α1-antitrypsin (α1AT).
In chronic obstructive pulmonary disease and bronchopulmonary dysplasia (BPD), polymorphonuclear