Journal
ANNALS OF BIOMEDICAL ENGINEERING
Volume 29, Issue 2, Pages 145-152Publisher
AMER INST PHYSICS
DOI: 10.1114/1.1349700
Keywords
endothelium; mechanical forces; thrombin receptor; endothelin-1; protein kinases; mRNA stability
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Funding
- NHLBI NIH HHS [HL18672, HL57352] Funding Source: Medline
- NINDS NIH HHS [NS23327] Funding Source: Medline
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Shear stress has been shown to regulate several genes involved in the thrombotic and proliferative functions of endothelial cells. Thrombin receptor (protease-activated receptor-1: PAR-1) increases at sites of vascular injury, which suggests an important role for PAR-1 in vascular diseases. However, the effect of shear stress on PAR-1 expression has not been previously studied. This work investigates effects of shear stress on PAR-1 gene expression in both human umbilical vein endothelial cells (HUVECs) and microvascular endothelial cells (HMECs). Cells were exposed to different shear stresses using a parallel plate flow system. Northern blot and flow cytometry analysis showed that shear stress downregulated PAR-1 messenger RNA (mRNA) and protein levels in both HUVECs and HMECs but with different thresholds. Furthermore, shear-reduced PAR-1 mRNA was due to a decrease of transcription rate, not increased mRNA degradation. Postshear stress release of endothelin-l in response to thrombin was reduced in HUVECs and HMECs. Moreover, inhibitors of potential signaling pathways applied during shear stress indicated mediation of the shear-decreased PAR-1 expression by protein kinases. In conclusion, shear stress exposure reduces PAR-1 gene expression in HMECs and HUVECs through a mechanism dependent in part on protein kinases, leading to altered endothelial cell functional responses to thrombin. (C) 2001 Biomedical Engineering Society.
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