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Mathew et al. Vessel Plus 2020;4:11 I http://dx.doi.org/10.20517/2574-1209.2019.35 Page 3 of 15
[20]
in distal pulmonary arteries, through the EC-derived fibroblast growth factor 2 (FGF-2) and IL-6 .
Pericyte-specific upregulation of CXCR (C-X-C chemokine receptor)-7 and transforming growth factor-β
receptor II (TGF-β RII) in patients with PAH are considered critical for their proliferation/migration
capacities and myogenic potentials. During the early phase, pericyte numbers increase in a CXCL (C-X-C
motif chemokine ligand)-12-dependent manner and later, the activation of the TGF-β signaling pathway
[21]
induces pericytes to differentiate into smooth muscle-like cells . Furthermore, reduced endothelial-
pericyte interactions result in progressive loss of small vessels in PAH. Increased expression of pyruvate
dehydrogenase kinase 4 (PDK4) gene and protein in PAH pericytes correlated with reduced mitochondrial
metabolism, higher rates of glycolysis, and hyperproliferation. Reducing PDK4 levels improved endothelial-
[22]
pericyte interactions, restored mitochondrial metabolism, and reduced cell proliferation . These studies
underscore the importance of EC and pericyte interactions in maintaining vascular homeostasis.

The disruption/apoptosis of ECs and accompanying endothelial caveolin-1 loss followed by enhanced
expression of caveolin-1 in SMCs, proliferation of antiapoptotic ECs and neointima formation have all
been reported in experimental PH and human PAH [23-26] . In a monocrotaline (MCT) + hypoxia model,
the enhanced expression of caveolin-1 revealed the presence of tyrosine 14-phosphorylated caveolin-1
[25]
(p-cav-1) and the loss of polymerase 1 and transcription factor also known as cavin-1 . Cavin-1
maintains the shape of caveolae and stabilizes caveolin-1 in caveolae. The loss of cavin-1 is indicative
of the flattening of caveolar structure. Cavin-1 knockout mice exhibit pathological lung changes such
as remodeled pulmonary vessels, PH and right ventricular hypertrophy (RVH). In addition, these mice
[27]
have an altered metabolic phenotype with insulin resistance . It is worth noting here that in cancer,
p-cav-1 has been shown to inactivate the growth inhibitory function of the caveolin-1 scaffolding domain
and facilitate cell migration [28-30] . These studies indicate that the disruption of endothelial caveolin-1 and
dysfunction of SMC caveolin-1 participate in the progression of PH. In addition, other factors such as
vascular endothelial growth factor (VEGF), epidermal growth factor, transforming growth factor β (TGFβ),
matrix metalloproteinases, bone morphogenic protein receptor type 2 (BMPR2) and Notch1 have all been
[31]
implicated in the pathophysiology of PAH . Thus, a large number of deregulated transcription factors and
proliferative pathways participate in the pathobiology of PH. Recent studies have shown that extracellular
vesicles (EVs) may have an important role in the pathogenesis of PH.

EVs
EVs have been isolated from body fluids such as blood, urine, saliva and cerebrospinal fluid. Initially EVs
were thought to be a means for cells to get rid of unwanted components. Currently, they are identified as
important mediators of intercellular communication. EVs participate in the exchange of lipids, proteins and
genetic material between cells, modulate immune, inflammatory and regenerative processes, and maintain
homeostasis. EVs are released from a variety of cells including platelets, erythrocytes, leukocytes, and ECs
maintain their different compositions and function. Most cell types generate EVs that play important roles
in various biological processes, including embryogenesis, tissue regeneration and immunomodulation.
They regulate the transfer of biological information both locally as well as remotely [32-35] . EVs include
exosomes (30-130 nm, in diameter), microparticles (MPs, also known as microvesicles, 100-1000 nm)
and apoptotic bodies (50-4000 nm). Apoptotic bodies are generated following activation of the apoptotic
pathway and cell death.

Exosomes
For exosome formation, endosomal membrane invagination captures cytosolic components within
intraluminal vesicles. Early endosomes then mature into late endosomes and accumulate intraluminal
vesicles, known as multivesicular bodies in their lumen. These multivesicular bodies either fuse with
lysosomes for degradation or with the plasma membrane and are released into the extracellular space as
exosomes [36,37] [Figure 1].