Effects of variable mechanical stimuli on vascular smooth muscle contractility
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Cells within the aortic wall are exposed to variable cyclic mechanical stimuli due to variability in blood pressure. Vascular smooth muscle cells, which have been shown to play an important role in maintaining aortic wall tension and stiffness, respond to mechanical stretch by reorganizing their cytoskeletal and contractile elements, which requires energy produced by the mitochondria. Mitochondria have also been implicated as a sensor in mechanotransduction pathways. We have shown recently that cells transduce fluctuations in their mechanical environment by reorganizing their cytoskeletal and mitochondrial networks, which can alter energy. Here we hypothesize that fluctuations in the mechanical environment regulates cell contractility through mitochondrial function. In order to test this hypothesis we first developed a cell stretching device that can deliver equi-biaxial stretch during simultaneous live imaging of subcellular structures. Cells were seeded on deformable silicone membranes which were stretched both monotonously and variably. To test the effect of substrate stiffness on mitochondrial function and to measure traction forces a gel with a tunable stiffness was added to the silicone membrane. Cells undergoing variable stretch had larger mitochondrial clusters and higher membrane potential than those undergoing monotonous stretch. To confirm the effects of increased mitochondrial membrane potential on contractility of vascular smooth muscle, aortic rings from Wistar Kyoto rats were stretched with variable and monotonous stretch patterns at physiological levels of variability and strain. Variable stretch maintained the contractile force of the vessel, while monotonous stretch decreased the force. Inhibition of ATP synthase function abated the difference between stretch patterns, implicating the role of the mitochondria during fluctuation-driven mechanotransduction. To measure the effects of variable stretch on aorta wall mechanics, the storage and loss moduli were computed for each cycle. While stretch pattern did not have an effect on vessel stiffness it did have an effect on the ratio of force generation to stiffness. Changes in force to stiffening ratio during contraction have implications on maintaining aortic wall mechanical homeostasis, particularly in diseased states characterized by increases in blood pressure variability such as hypertension.