AUTHOR=Ranjan Prabhat , Kumari Rajesh , Goswami Sumanta Kumar , Li Jing , Pal Harish , Suleiman Zainab , Cheng Zhongjian , Krishnamurthy Prasanna , Kishore Raj , Verma Suresh Kumar 

TITLE=Myofibroblast-Derived Exosome Induce Cardiac Endothelial Cell Dysfunction

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.676267

DOI=10.3389/fcvm.2021.676267

ISSN=2297-055X

ABSTRACT=<p><bold>Background:</bold> Endothelial cells (ECs) play a critical role in the maintenance of vascular homeostasis and in heart function. It was shown that activated fibroblast-derived exosomes impair cardiomyocyte function in hypertrophic heart, but their effect on ECs is not yet clear. Thus, we hypothesized that activated cardiac fibroblast-derived exosomes (FB-Exo) mediate EC dysfunction, and therefore modulation of FB-exosomal contents may improve endothelial function.</p><p><bold>Methods and Results:</bold> Exosomes were isolated from cardiac fibroblast (FB)-conditioned media and characterized by nanoparticle tracking analysis and electron microscopy. ECs were isolated from mouse heart. ECs were treated with exosomes isolated from FB-conditioned media, following FB culture with TGF-β1 (TGF-β1-FB-Exo) or PBS (control) treatment. TGF-β1 significantly activated fibroblasts as shown by increase in collagen type1 α1 (<italic>COL1</italic>α<italic>1</italic>), periostin (<italic>POSTN</italic>), and fibronectin (<italic>FN1</italic>) gene expression and increase in Smad2/3 and p38 phosphorylation. Impaired endothelial cell function (as characterized by a decrease in tube formation and cell migration along with reduced <italic>VEGF-A, Hif1</italic>α<italic>, CD31</italic>, and <italic>angiopoietin1</italic> gene expression) was observed in TGF-β1-FB-Exo treated cells. Furthermore, TGF-β1-FB-Exo treated ECs showed reduced cell proliferation and increased apoptosis as compared to control cells. TGF-β1-FB-Exo cargo analysis revealed an alteration in fibrosis-associated miRNAs, including a significant increase in miR-200a-3p level. Interestingly, miR-200a-3p inhibition in activated FBs, alleviated TGF-β1-FB-Exo-mediated endothelial dysfunction.</p><p><bold>Conclusions:</bold> Taken together, this study demonstrates an important role of miR-200a-3p enriched within activated fibroblast-derived exosomes on endothelial cell biology and function.</p>