Abstract
Cells in vascular walls are exposed to blood pressure variability (BPV)-induced cycle-by-cycle fluctuations in mechanical forces which vary considerably with pathology. For example, BPV is elevated in hypertension but reduced under anesthesia. We hypothesized that the extent of mechanical fluctuations applied to vascular smooth muscle cells (VSMCs) regulates mitochondrial network structure near the percolation transition, which also influences ATP and reactive oxygen species (ROS) production. We stretched VSMCs in culture with cycle-by-cycle variability in area strain ranging from no variability (0%), as in standard laboratory conditions, through abnormally small (6%) and physiological (25%) to pathologically high (50%) variability mimicking hypertension, superimposed on 0.1 mean area strain. To explore how oxidative stress and ATP-dependent metabolism affect mitochondria, experiments were repeated in the presence of hydrogen peroxide and AMP-PNP, an ATP analog and competitive inhibitor of ATPases. Physiological 25% variability maintained activated mitochondrial cluster structure at percolation with a power law distribution and exponent matching the theoretical value in 2 dimensions. The 25% variability also maximized ATP and minimized cellular and mitochondrial ROS production via selective control of fission and fusion proteins (mitofusins, OPA1 and DRP1) as well as through stretch-sensitive regulation of the ATP synthase and VDAC1, the channel that releases ATP into the cytosol. Furthermore, pathologically low or high variability moved mitochondria away from percolation which reduced the effectiveness of the electron transport chain by lowering ATP and increasing ROS productions. We conclude that normal BPV is required for maintaining optimal mitochondrial structure and function in VSMCs.
Highlights
Cells in vascular walls are exposed to blood pressure variability (BPV)-induced cycle-by-cycle fluctuations in mechanical forces which vary considerably with pathology
We recently reported that ATP production, monitored via the mitochondrial membrane potential, was maintained at a high level in vascular smooth muscle cells (VSMCs) when they were exposed to a variable-amplitude cyclic stretch pattern mimicking normal BPV compared with monotonous constant-amplitude cyclic stretch[24]
The mitochondrial structure was first characterized by the average cluster size per cell (Fig. 1B) which was the largest under V25 in control cells and the smallest under V50 which did not differ from V0
Summary
Cells in vascular walls are exposed to blood pressure variability (BPV)-induced cycle-by-cycle fluctuations in mechanical forces which vary considerably with pathology. We hypothesized that the extent of mechanical fluctuations applied to vascular smooth muscle cells (VSMCs) regulates mitochondrial network structure near the percolation transition, which influences ATP and reactive oxygen species (ROS) production. In response to localized oxidative stress, inter-mitochondrial communication is promoted by a cell-wide phase transition in mitochondrial depolarization when mitochondrial clusters with reactive oxygen species (ROS) beyond a critical threshold level tend to form a large percolation-like cluster[10]. These studies link mitochondrial function to the complexity and criticality of mitochondrial structure. Images were taken after 4 hours of equi-biaxial stretch with a mean peak strain amplitude of 0.1 and superimposed cycle-by-cycle variabilities of 0%, 6%, 25% and 50% denoted respectively by V0, V6, V25 and
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