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Li M, Tan Y, Stenmark KR, et al. High Pulsatility Flow Induces Acute Endothelial Inflammation through Overpolarizing Cells to Activate NF-κB. Cardiovasc Eng Technol. 2013;4(1):26-38doi: 10.1007/s13239-012-0115-5.
Li, M., Tan, Y., Stenmark, K. R., & Tan, W. (2013). High Pulsatility Flow Induces Acute Endothelial Inflammation through Overpolarizing Cells to Activate NF-κB. Cardiovascular engineering and technology, 4(1), 26-38. https://doi.org/10.1007/s13239-012-0115-5
Li, Min, et al. "High Pulsatility Flow Induces Acute Endothelial Inflammation through Overpolarizing Cells to Activate NF-κB." Cardiovascular engineering and technology vol. 4,1 (2013): 26-38. doi: https://doi.org/10.1007/s13239-012-0115-5
Li M, Tan Y, Stenmark KR, Tan W. High Pulsatility Flow Induces Acute Endothelial Inflammation through Overpolarizing Cells to Activate NF-κB. Cardiovasc Eng Technol. 2013 Mar;4(1):26-38. doi: 10.1007/s13239-012-0115-5. PMID: 23667401; PMCID: PMC3646301.
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Cardiovasc Eng Technol. 2013 Mar;4(1):26-38. doi: 10.1007/s13239-012-0115-5.

High Pulsatility Flow Induces Acute Endothelial Inflammation through Overpolarizing Cells to Activate NF-κB.

Cardiovascular engineering and technology

Min Li, Yan Tan, Kurt R Stenmark, Wei Tan

Affiliations

  1. Department of Pediatrics, University of Colorado at Denver, Aurora, CO 80045.

PMID: 23667401 PMCID: PMC3646301 DOI: 10.1007/s13239-012-0115-5

Abstract

Large artery stiffening and small artery inflammation are both well-known pathological features of pulmonary and systemic hypertension, but the relationship between them has been seldom explored. We previously demonstrated that stiffening-induced high pulsatility flow stimulated a pro-inflammatory response in distal pulmonary artery endothelial cells (PAEC). Herein, we hypothesized that high pulsatility flow activated PAEC pro-inflammatory responses are mediated through cell structural remodeling and cytoskeletal regulation of NF-κB translocation. To test this hypothesis, cells were exposed to low and high pulsatility flows with the same mean physiological flow shear stress. Results showed that unidirectional, high pulsatility flow led to continuous, high-level NF-κB activation, whereas low pulsatility flow induced only transient, minor NF-κB activation. Compared to cell shape under the static condition, low pulsatility flow induced cell elongation with a polarity index of 1.7, while high pulsatility flow further increased the cell polarity index to a value greater than 3. To explore the roles of cytoskeletal proteins in transducing high flow pulsatility into NF-κB activation, PAECs were treated with drugs that reduce the synthesis-breakdown dynamics of F-actin or microtubules (cytochalasin D, phalloidin, nocodazole, and taxol) prior to flow. Results showed that these pre-treatments suppressed NF-κB activation induced by high pulsatility flow, but drugs changing dynamics of F-actin enhanced NF-κB activation even under low pulsatility flow. Taxol was further circulated in the flow to examine its effect on cells. Results showed that circulating taxol (10nM) reduced PAEC polarity, NF-κB activation, gene expression of pro-inflammatory molecules (ICAM-1 and VCAM-1), and monocyte adhesion on the PAECs under high pulsatility flow. Therefore, taxol effectively reduced high pulsatility flow-induced PAEC overpolarization and pro-inflammatory responses via inhibiting cytoskeletal remodeling. This study suggests that stabilizing microtubule dynamics might bea potential therapeutic means of reducing endothelial inflammation caused by high pulsatility flow.

Keywords: NF-kB; cytoskeleton; endothelial cells; high pulsatility flow; inflammation; pulmonary vascular hypertension; vascular stiffening

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