RETRACTED ARTICLE: High Pulsatility Flow Promotes Vascular Fibrosis by Triggering Endothelial EndMT and Fibroblast Activation.

Autor: Elliott WH; Department of Mechanical Engineering, University of Colorado at Boulder, 1111 Engineering Dr, ECME 114, Boulder, CO 80309-0427 USA., Tan Y; Department of Mechanical Engineering, University of Colorado at Boulder, 1111 Engineering Dr, ECME 114, Boulder, CO 80309-0427 USA., Li M; Department of Pediatrics, University of Colorado at Denver, Aurora, CO 80045 USA., Tan W; Department of Mechanical Engineering, University of Colorado at Boulder, 1111 Engineering Dr, ECME 114, Boulder, CO 80309-0427 USA.; Department of Pediatrics, University of Colorado at Denver, Aurora, CO 80045 USA.
Jazyk: angličtina
Zdroj: Cellular and molecular bioengineering [Cell Mol Bioeng] 2015 Mar 19; Vol. 8 (2), pp. 285-295. Date of Electronic Publication: 2015 Mar 19 (Print Publication: 2015).
DOI: 10.1007/s12195-015-0386-7
Abstrakt: Vascular fibrosis, the formation of excess fibrous tissue on the blood vessel wall, is characterized by unmitigated proliferation of fibroblasts or myofibroblast-like cells exhibiting α-smooth-muscle-actin in vessel lumen and other vascular layers. It likely contributes to vascular unresponsiveness to conventional therapies. This paper demonstrates a new flow-induced vascular fibrosis mechanism. Using our developed flow system which simulates the effect of vessel stiffening and generates unidirectional high pulsatility flow (HPF) with the mean shear flow at a physiological level, we have shown that HPF caused vascular endothelial dysfunction. Herein, we further explored the role of HPF in vascular fibrosis through endothelial-to-mesenchymal transdifferentiation (EndMT). Pulmonary arterial endothelial cells (ECs) were exposed to steady flow and HPF, which have the same physiological mean fluid shear but different in flow pulsatility. Cells were analyzed after being conditioned with flows for 24 or 48 h. HPF was found to induce EndMT of cells after 48 h stimulation; cells demonstrated drastically decreased expression in EC marker CD31, as well as increased transforming growth factor β, α-SMA, and collagen type-I, in both gene and protein expression profiles. Using the flow media from HPF-conditioned endothelial culture to cultivate arterial adventitial fibroblasts (AdvFBs) and ECs respectively, we found that the conditioned media respectively enhanced migration, proliferation and α-SMA expression of AdvFBs, and induced EndMT of ECs. It was further revealed that cells exposed to HPF exhibited much higher percentage of caspase-positive cells compared to those exposed to steady flow. Apoptotic cells together with remaining, caspase-negative cells suggested the presence of apoptosis-resistant dysfunctional ECs which likely underwent EndMT process and perpetuated fibrosis throughout vascular tissues. Therefore, our results indicate that prolonged HPF stimuli induce vascular fibrosis through triggering EndMT and EC-mediated AdvFB activation and migration, which follows initial endothelial inflammation, dysfunction and apoptosis.
(© Biomedical Engineering Society 2015.)
Databáze: MEDLINE
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