@article{3170768,
    title = "Vascular endothelial-cadherin downregulation as a feature of endothelial
transdifferentiation in monocrotaline-induced pulmonary hypertension",
    author = "Nikitopoulou, Ioanna and Orfanos, Stylianos E. and Kotanidou, Anastasia and and Maltabe, Violetta and Manitsopoulos, Nikolaos and Karras, Panagiotis and and Kouklis, Panos and Armaganidis, Apostolos and Maniatis, Nikolaos A.",
    journal = "American Journal of Physiology - Lung Cellular and Molecular Physiology",
    year = "2016",
    volume = "311",
    number = "2",
    pages = "L352-L363",
    publisher = "AMER PHYSIOLOGICAL SOC",
    issn = "1040-0605, 1522-1504",
    doi = "10.1152/ajplung.00156.2014",
    keywords = "pulmonary arterial hypertension; endothelial-to-mesenchymal transition;
monocrotaline; vascular endothelial-cadherin; endothelin-1",
    abstract = "Increased pulmonary vascular resistance in pulmonary hypertension (PH)
is caused by vasoconstriction and obstruction of small pulmonary
arteries by proliferating vascular cells. In analogy to cancer, subsets
of proliferating cells may be derived from endothelial cells
transitioning into a mesenchymal phenotype. To understand phenotypic
shifts transpiring within endothelial cells in PH, we injected rats with
alkaloid monocrotaline to induce PH and measured lung tissue levels of
endothelial-specific protein and critical differentiation marker
vascular endothelial (VE)-cadherin. VE-cadherin expression by
immonoblotting declined significantly 24 h and 15 days postinjection to
rebound to baseline at 30 days. There was a concomitant increase in
transcriptional repressors Snail and Slug, along with a reduction in
VE-cadherin mRNA. Mesenchymal markers alpha-smooth muscle actin and
vimentin were upregulated by immunohistochemistry and immunoblotting,
and alpha-smooth muscle actin was colocalized with endothelial marker
platelet endothelial cell adhesion molecule-1 by confocal microscopy.
Apoptosis was limited in this model, especially in the 24-h time point.
In addition, monocrotaline resulted in activation of protein kinase
B/Akt, endothelial nitric oxide synthase (eNOS), nuclear factor
(NF)-kappa B, and increased lung tissue nitrotyrosine staining. To
understand the etiological relationship between nitrosative stress and
VE-cadherin suppression, we incubated cultured rat lung endothelial
cells with endothelin-1, a vasoconstrictor and pro-proliferative agent
in pulmonary arterial hypertension. This resulted in activation of eNOS,
NF-kappa B, and Akt, in addition to induction of Snail, downregulation
of VE-cadherin, and synthesis of vimentin. These effects were blocked by
eNOS inhibitor N-omega-nitro-Larginine methyl ester. We propose that
transcriptional repression of VE-cadherin by nitrosative stress is
involved in endothelial-mesenchymal transdifferentiation in experimental
PH."
}