Mechanical control of cation channels in the myogenic response

Abstract

Microcirculatory vessel response to changes in pressure, known as the myogenic response, is a key component of a tissue's ability to regulate blood flow. Experimental studies have not clearly elucidated the mechanical signal in the vessel wall governing steady-state reduction in vessel diameter upon an increase in intraluminal pressure. In this study, a multiscale computational model is constructed from established models of vessel wall mechanics, vascular smooth muscle (VSM) force generation, and VSM Ca 2ϩ handling and electrophysiology to compare the plausibility of vessel wall stress or strain as an effective mechanical signal controlling steady-state vascular contraction in the myogenic response. It is shown that, at the scale of a resistance vessel, wall stress, and not stretch (strain), is the likely physiological signal controlling the steady-state myogenic response. (28), and large-conductance, Ca 2ϩ -activated K ϩ (BK Ca ) channel, which has a large influence on the level of membrane polarization (17). Many of these studies identifying channels with mechanotransductive qualities have investigated the channels in isolation by patch clamping and exposure to exogenous substances or mechanical conditions representative of those thought to be present in the intact cellular environment. Foundational work on mechanotransductive channels focused on how the strain or tension directly affects channel-gating probabilities (39 -41). It is clear that many of these channels respond to mechanical stimulation; however, it cannot be determined from these studies whether vessel wall stress or strain is the controlling mechanical stimulus and how these stimuli may control channel function in the myogenic response. Therefore, to understand how these channels are controlled and play a role in the acute regulatory response to pressure through the complex interactions in an intact single vessel, an integrated theoretical model taking into consideration VSM electrophysiology, VSM force generation, and vessel wall mechanics must be employed. Such a theoretical platform is a valuable hypothesis-testing method aimed at assessing which underlying channel function or set of functions is sufficient to describe the observed whole-vessel response and will be important in determining future experimental design.Several detailed models of VSM electrophysiology have been previously developed and used in integrated models of acute regulation of arteriolar vessels. Yang et al. (53,54) -induced Ca 2ϩ release and cytosolic buffering. Simulation protocols utilizing a depolarizing voltage pulse and applied strain were used to interrogate the model function with respect to qualitative and quantitative features from experimental studies of VSM cells. Koenigsberger et al. (24,25) investigated the myogenic response and oscillatory behavior of microvessels known as vasomotion with a similar model but focused on the influence of stretch-activated channels that were formulated to be activated by stress in the vessel. VSM force generation based on cy...

Predicted effects of nitric oxide and superoxide on the vasoactivity of the afferent arteriole

“…Several theoretical studies, including our previous model of the myogenic response in the rat afferent arteriole, have demonstrated the plausibility of this mechanism (4,11). The present model, in addition, accounts for recent evidence that ROS production increases in response to elevated pressure (46,56).…”

“…The cytosolic concentrations of K ϩ , Na ϩ , Cl Ϫ , and Ca 2ϩ as a function of time are determined by considering the sum of their respective fluxes into the cytosol and integrating the following differential equations: (4) where F is Faraday's constant and vol cyt and vol cyt,Ca denote the total volume of the cytosol and the volume that is available to Ca 2ϩ , respectively. The convention adopted in this study is that exit of positive charge from the cell is a positive current.…”

Regulation of Coronary Blood Flow

“…Molecular entities that transduce stretch of the vascular wall into depolarization and constriction are not entirely clear, but may include ion channels themselves. Modeling suggests that channels permeable to Ca 2+ and/or Na + in smooth muscle are activated in proportion to wall stress (149). Elegant experiments have demonstrated that in single coronary artery smooth muscle cells from the porcine coronary artery, graded stretch is associated with the activation of a cation current and concomitant increases in intracellular Ca 2+ [(226,991) Fig.…”

Multiscale Modeling and Data Integration in the Virtual Physiological Rat Project

“…The VSM electrophysiology and ion handling model was originally coded in Fortran while the remaining models were coded in MATLAB and JSim. All models had to be recoded into MATLAB in Carlson and Beard6 which limited the sharing of this model with the wider community. Translation from SemSim to MML and CellML is currently supported within SemGen and translation to MATLAB is in development.

Figure 3Integrative cellular based vessel model of the steady-state myogenic response.

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