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Schistosoma Mansoni-Induced Shedding Of Extracellular Vesicles From Lung Microvascular Endothelial Cells

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY(2021)

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摘要
Introduction: Schistosomiasis-associated Pulmonary Arterial Hypertension (Sch-PAH) is a life-threatening complication of chronic Schistosoma mansoni infection. Sch-PAH is marked by obliteration and remodeling of the pulmonary vasculature in response to S. mansoni eggs. Remodeled and occluded vessels increase vascular resistance and can lead to heart failure and death. Currently, there are no target therapies for the treatment of Sch-PAH. Hypothesis: S. mansoni egg-derived antigens alter pulmonary endothelial cell (EC) Caveolin-1 (Cav-1) expression and phosphorylation contributing to the loading and shedding of extracellular vesicles (EVs), which in turn stimulates abnormal EC survival leading to Sch-PAH. Methods/Results: Immunohistology and western blot analysis of lungs from S. mansoni -infected mice revealed a significant decrease in Cav-1 expression in the egg-dependent granuloma area when compared to uninfected control animals, indicating that local S. mansoni -associated molecules and inflammatory mediators contribute to Cav-1 depletion. Previously we showed that upon vascular injury, Cav-1 deficiency leads to the survival of an abnormal EC phenotype through an unclear mechanism. Analysis of survival-associated genes in isolated lung ECs from Flk1 +/GFP ; Cav1 -/- mice, revealed a high expression of the anti-apoptotic BIRC2 and BIRC5 (known as c-IAP2 and surviving, respectively) when compared to control ECs. Interesting, in vitro exposure to the major S. mansoni egg antigen, Sm-p40 (1 μg/mL), induced time-dependent phosphorylation of Cav-1 Tyr14 in human lung microvascular ECs (HMVEC-L; 228.2 +/- 38.28% of control; p<0.05; n=4), which culminated in c-IAP2 expression. Furthermore, Sm-p40 treatment of HMVEC-L increased ERK1/2 phosphorylation, which in presence of pro-inflammatory mediators IL-6, TNF-a, and ATP, significantly increased the shedding of EVs implicating P-ERK1/2 in the mechanism of shedding of Cav-1-EVs. Conclusions: This work is uncovering the biological role and potential translational relevance of pathogen-induced EC-Cav-1 depletion via shedding of EVs during Sch-PAH.
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