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Page 8 of 15 Mathew et al. Vessel Plus 2020;4:11 I http://dx.doi.org/10.20517/2574-1209.2019.35

could then facilitate proliferation of anti-apoptotic ECs. The loss of endothelial caveolin-1, PECAM-1, vWF
and vascular endothelial cadherin, which is indicative of endothelial disruption, has been described in
experimental and human PAH [16,24,100] . Furthermore, increased levels of endothelial MPs carrying vascular
endothelial cadherin and PECAM-1 were shown to be associated with hemodynamic severity of PAH [101] .
In addition, BMPR2 loss has been reported in experimental PH and in patients with IPAH without the
BMPR2 mutation, and to a lesser degree, in patients with “associated” PAH [102,103] . Interestingly, the loss
of endothelial caveolin-1 and oxidative stress leads to reduced BMPR2 expression, increased TGFß-
derived Smad 2/3 signaling and pulmonary vascular remodeling [104] . Oliveira et al. [105] recently showed that
in the Sugen + hypoxia model of PH in rats and human PAH, endothelial caveolin-1 loss accompanied
by increased plasma levels of caveolin-1 EVs and TGFβ, indicating that the endothelial caveolin-1 loss
contributes to increased TGFβ signaling, leads to EC proliferation, vascular remodeling and PAH.
Caveolin-1 appears to be a plasma biomarker of vascular injury and a key determinant of TGFβ-induced
vascular remodeling. It is possible then that the increased levels of EVs containing caveolin-1 in plasma
could, in part, be responsible for enhanced expression of caveolin-1 in SMCs observed in IPAH, HPAH and
PAH associated with drug toxicity and congenital heart defects [23,24,100,106] .

Recent studies have shown that human pulmonary arterial ECs can efficiently incorporate EVs transmitted
by human pulmonary arterial SMCs and translate their mRNA cargo. These EVs enriched in Zeb1 and
TGF-β superfamily ligands contribute to endothelial mesenchymal transition (EndMT), thus facilitating
disease progression [107] . However, partial EndMT is a physiological process necessary for angiogenesis. In
partial EndMT, ECs do not separate from their neighboring cells [108] . Figure 3 (as shown on page 9) depicts
the inter-relationship between ECs and SMCs, and the role played by EVs in PH.

Interestingly, cigarette smoking results in the release of endothelial EVs with spermine enrichment
2+
both on the surface as well as in the cytosol and activates a Ca -sensing receptor leading to pulmonary
vasoconstriction, SMC proliferation and PH [109] . These results strongly support endothelial injury and
disruption underlying the release of EVs. Depending on the cargo, EVs participate in EC-SMC crosstalk in
physiological or pathological conditions.

PH, MSC AND MESENCHYMAL EVS
A number of studies have shown the beneficial effects of MSC therapy in experimental models of PH.
Intravenous treatment with adipose-derived MSCs improved MCT-induced PH in rats. In addition,
adipose-derived MSCs in co-culture with MCT-treated human pulmonary arterial ECs exhibit increased
cell proliferation and expression of VEGF [110] . Bone marrow-derived MSCs over-expressing eNOS
attenuated MCT-induced PH in rats [111] , and MSCs expressing increased hemoxygenase (HO)-1 reversed
hypoxia-induced PH in mice [112] . In addition, transplantation with bone marrow-derived MSCs transduced
with prostacyclin synthase, and therapy with adiponectin gene modified adipose MSCs significantly
attenuated MCT-induced PH, RVH, pulmonary vascular thickening and survival in rats. In in vitro
studies, the inhibitory effect of adiponectin on the proliferation of pulmonary arterial SMCs obtained
from rats with MCT-induced PH was shown to be dependent on the regulation of the AMPK/BMP/Smad
pathway [113,114] . Interestingly, intravenous administration of bone marrow-derived MSCs from donor rats
with MCT-induced PH to the recipient rat with MCT-induced PH resulted in attenuation of PH and RVH,
and normalization of right ventricular function. Bone marrow-derived MSCs from MCT rats produced
more VEGF compared to controls [115] . In addition, adipose tissue-derived MSC therapy in rats with shunt
flow-induced hyperkinetic PAH was attenuated via increased expression of hepatocyte growth factor and
eNOS promoting angiogenesis in the injured lungs [116] .

Importantly, female bone marrow-derived MSCs were found to attenuate MCT-induced PH and RVH
in mice better than male MSCs. Female MSCs had increased expression of glyceraldehyde-3-phospahte