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Page 6 of 15 Mathew et al. Vessel Plus 2020;4:11 I http://dx.doi.org/10.20517/2574-1209.2019.35
[57]
leukocyte-derived exosomes acquire surface-bound elastase that degrade extracellular matrix . In sickle
cell disease, inflammasome-dependent shedding of platelet EVs carrying IL-1β and caspase-1 activate
neutrophils and other vascular cells to form large platelet-neutrophil aggregates that occlude pulmonary
arteries. The level of circulating platelet EVs correlate with disease severity. Increased circulating platelets
and erythroid MPs were observed in untreated children with sickle cell disease; hydroxyurea therapy,
however, normalized MP levels [58,59] . In vitro studies have shown that high arterial stress results in platelet
[60]
activation and release of prothrombogenic EVs in the blood . In cell culture studies, platelet MPs have
[61]
been shown to induce SMC proliferation in a platelet derived growth factor-independent manner . In
addition, circulating platelet-derived EVs induced increased production of cytokines (IL-1, IL-6, and IL-8),
leading to immune modulation, endothelial dysfunction and remodeling. In contrast, neutrophil-derived
[62]
EVs enhance the biosynthesis of specialized pro-resolving mediators . MPs from patients with metabolic
syndrome decrease NO production in ECs in culture, independent of oxidative stress. Furthermore,
[63]
injection of MPs in mice resulted in reduced eNOS synthesis and impaired vascular relaxation . In
addition, tissue factor containing MPs are proinflammatory mediators between increased glucose levels and
[64]
diabetic vasculopathy . In cancer, EVs promote tumor growth, metastasis and resistance to therapy; and
the activation of oncogene signaling pathway can increase EV production. These EVs transfer oncoproteins
and facilitate tumor angiogenesis, immunosuppression and metastasis [65,66] . In vitro studies have shown large
[67]
EVs carrying caveolin-1 in cancer cells to be involved in metastasis . Thus, the function of MPs depends
on the cell types that they originate from and their pathophysiological state.

Mesenchymal stem cells (MSC) are the best cell types for tissue regenerative therapies. They can be
readily derived, propagated and differentiated into a variety of cell types. They modulate several biological
functions such as tissue repair, downregulation of inflammatory responses, and modulation of the immune
system. MSC-derived exosomes have protective effects on ischemia-reperfusion injury via inhibition
of cell apoptosis and inflammatory responses [68,69] . Furthermore, treatment with multipotent stem cells
[71]
[70]
showed strong regenerative capabilities in animal models of myocardial ischemia , stroke , and
[72]
diabetes . Recent studies have suggested that MSC-derived EVs containing miRNAs might promote cell
[73]
and tissue repair, and regeneration . Similar to the biological activities of MSC, MSC-derived exosomes
[74]
recover and regenerate the damaged tissues and restore homeostasis . MSC-exosomes reduce oxidative
[75]
stress and prevent adverse remodeling in hearts subjected to ischemia-perfusion ; and placental MSC-
derived exosomes promote new blood vessel formation and angiogenesis within the placenta under
[76]
low oxygen conditions . Interestingly, female bone marrow derived MSCs exhibit higher therapeutic
efficacy compared with male MSCs in reducing neonatal hyperoxia-induced lung inflammation, vascular
remodeling and PH in a rat model of BPD. Female MSCs express higher levels of VEGF and IL-10, and are
better in attenuating PH and improving pulmonary vascular remodeling. The effects on angiogenesis and
[77]
alveolarization however, were similar in female and male MSC treatment . In an ischemia-reperfusion
injury model, female MSC infusion revealed a greater degree of myocardial recovery compared to male
[78]
MSC. The protective effect of female MSCs appears to be related to lower levels of TNFR1 . In addition,
17β-estradiol-treated cardiac stem cells increased the expression of VEGF and SDF-1, and decreased
[79]
caspase3 resulting in improved myocyte survival after acute ischemia perfusion injury . These studies
suggest that the superior cell survival effect of female MSCs may be dependent on estrogen levels. In
contrast, male muscle-derived stem cells display better cartilage regeneration potential compared with their
[80]
female counterparts . Thus, these gender differences may be tissue-specific and female MSCs appear to
provide better protection in cardiovascular and lung diseases.

PULMONARY HYPERTENSION AND EXTRACELLULAR VESICLES
Altered immunity, platelet activation, vascular inflammation, endothelial dysfunction and thrombo-
embolic complications are well known features of PH. Platelet MPs have been shown to roll over ECs to
[81]
deliver CCL5 . Importantly, CCL5 is a chemo-attractant for monocytes and T cells. In severe PAH, ECs