Inhibition of stretch-activated ion channels on endothelial cells disrupts nitric oxide-mediated arterial outward remodeling

Outward arterial remodeling is a physiological response to accommodate chronically elevated blood flow and requires endothelial cells (ECs) and expression of endothelial nitric oxide synthase (eNOS). ECs may sense elevated flow via stretch-activated ion channels (SACs). We evaluated the role of SACs in regulation of flow-induced arterial expansion and eNOS expression by ECs. A high-flow environment was created in the common carotid arteries (CCAs) of mice via contralateral common carotid artery (CCA) ligation. Either streptomycin for SAC blockade or saline for placebo was delivered to the mice. CCAs were harvested for morphometric analysis 7 days post procedure. Cultured ECs were exposed to flow with wall shear stresses (WSSs) of 1.5-10 Pa for 24 h in presence or absence of streptomycin. Immunofluorescent staining was used for eNOS quantification. In vivo, CCA expansion in streptomycin-treated mice (n = 7) was significantly less than in the placebo-treated group (n = 8) (p = 0.015). In vitro, streptomycin exposure significantly inhibited eNOS expression at WSS >2.5 Pa (p = 0.001) while not affecting eNOS expression at baseline WSS (1.5-2.5 Pa). Blockade of SACs with streptomycin impairs outward arterial remodeling and eNOS expression at high WSSs. Activation of SACs under elevated WSS may contribute to vessel expansion by upregulating eNOS in ECs.