Key result
Physiologic cyclic strain significantly downregulated thrombomodulin expression in human aortic endothelial cells while upregulating its release in a time-, dose-, and frequency-dependent manner.
Physiologic cyclic strain downregulates thrombomodulin expression while upregulating its release in human aortic endothelial cells, highlighting complex hemodynamic regulation of vascular homeostasis.
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Hypothesis-generating for hemodynamic effects on endothelial thrombomodulin; prospective studies needed before clinical translation.
BACKGROUND AND OBJECTIVES: Thrombomodulin (TM), an integral membrane glycoprotein expressed on the lumenal surface of vascular endothelial cells, promotes anti-coagulant and anti-inflammatory properties. Release of functional TM from the endothelium surface into plasma has also been reported. Much is still unknown however about how endothelial TM is regulated by physiologic hemodynamic forces (and particularly cyclic strain) intrinsic to endothelial-mediated vascular homeostasis. METHODS: This study employed human aortic endothelial cells (HAECs) to investigate the effects of equibiaxial cyclic strain (7.5%, 60 cycles/min, 24 hrs), and to a lesser extent, laminar shear stress (10 dynes/cm2, 24 hrs), on TM expression and release. Time-, dose- and frequency-dependency studies were performed. RESULTS: Our initial studies demonstrated that cyclic strain strongly downregulated TM expression in a p38- and receptor tyrosine kinase-dependent manner. This was in contrast to the upregulatory effect of shear stress. Moreover, both forces significantly upregulated TM release over a 48 hr period. With continuing focus on the cyclic strain-induced TM release, we noted both dose (0-7.5%) and frequency (0.5-2.0 Hz) dependency, with no attenuation of strain-induced TM release observed following inhibition of MAP kinases (p38, ERK-1/2), receptor tyrosine kinase, or eNOS. The concerted impact of cyclic strain and inflammatory mediators on TM release from HAECs was also investigated. In this respect, both TNFα (100 ng/ml) and ox-LDL (10-50 µg/ml) appeared to potentiate strain-induced TM release. Finally, inhibition of neither MMPs (GM6001) nor rhomboids (3,4-dichloroisocoumarin) had any effect on strain-induced TM release. However, significantly elevated levels (2.1 fold) of TM were observed in isolated microparticle fractions following 7.5% strain for 24 hrs. CONCLUSIONS: A preliminary in vitro investigation into the effects of cyclic strain on TM in HAECs is presented. Physiologic cyclic strain was observed to downregulate TM expression, whilst upregulating in a time-, dose- and frequency-dependent manner the release of TM.
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Martin et al. (2014) studied this question. Equibiaxial cyclic strain vs. Static conditions (0% strain) was evaluated on Thrombomodulin (TM) expression and release (41% reduction in TM mRNA and 43.5% reduction in protein expression, p=≤0.05). Physiologic cyclic strain significantly downregulated thrombomodulin expression in human aortic endothelial cells while upregulating its release in a time-, dose-, and frequency-dependent manner.
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