Abstract
The endothelium is an attractive drug target and an important site of adverse drug reactions. Endothelial dysfunction is strongly associated with inflammation and contributes to drug-induced cardiovascular toxicity. Endothelial cells in the circulation are exposed to haemodynamic forces including shear stress. Including shear stress may improve future endothelial cell drug discovery or toxicity screening. Piezo-1 is required for endothelial cells to respond to shear stress. In this study, we investigated whether a small molecule activator of Piezo-1, Yoda-1, can mimic the effect of laminar flow-induced shear stress on endothelial cell inflammation, and endothelial cytotoxicity in response to the chemotherapy agent, doxorubicin.First, we tested whether Yoda-1 could mimic the effects of shear stress of expression of the endothelial adhesion molecules, ICAM-1 and VCAM-1. Human umbilical vein endothelial cells (HUVEC) were cultured in static conditions (with or without Yoda-1) or under laminar flow-induced shear stress (5 dyn/cm2). Yoda-1 and laminar flow had similar anti-inflammatory effects, reducing the ability of TNF-α to induce ICAM-1 and VCAM-1 expression. We then tested whether Yoda-1 could mimic the effect of shear stress on doxorubicin-induced cytotoxicity. Both laminar flow and Yoda-1 treatment of static cultures increased the cytotoxicity of doxorubicin. These findings show that Piezo-1 activation with Yoda-1 in static culture leads to an endothelial cell phenotype that mimics endothelial cells under laminar flow. Pharmacological activation of Piezo-1 may be a useful approach to mimic constant shear stress in static cultures, which may improve endothelial drug discovery and toxicity testing.
Highlights
Endothelial cells play a key role in vascular homeostasis, including regulation of vascular tone, inflammation and haemostasis [1]
We tested whether Yoda-1 could mimic the effect of shear stress on doxorubicin-induced cytotoxicity. Both laminar flow and Yoda-1 treatment of static cultures increased the cytotoxicity of doxorubicin. These findings show that Piezo-1 activation with Yoda-1 in static culture leads to an endothelial cell phenotype that mimics endothelial cells under laminar flow
Mimicking in vivo conditions such as shear stress on endothelial cells in vitro is an important consideration in endothelial drug discovery and toxicity testing, as a means of generating endothelial cells that more closely resemble the in vivo endothelium
Summary
Endothelial cells play a key role in vascular homeostasis, including regulation of vascular tone, inflammation and haemostasis [1]. Endothelial dysfunction is strongly associated with proinflammatory and prothrombotic disease states, such as the initiation and progression of atherosclerosis [2]. Endothelial dysfunction is promoted by risk factors associated with cardiovascular disease, including diabetes, hypercholesterolemia, hypertension and smoking [3]. Endothelial cells in the normal circulation are exposed to haemodynamic forces including shear stress, a frictional force acting parallel to the wall [5]. Constant laminar shear stress has been reported to be antiinflammatory, for example by reducing the increase in vascular cell adhesion molecule-1 (VCAM-1) expression in response to tumour necrosis factor-alpha (TNF-α) [9,10,11]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have