title: 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(2+) 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. The model is then used to test nine candidate VSM stress-controlled channel variants by fitting two separate sets of steady-state myogenic response data. The channel variants include nonselective cation (NSC), supplementary Ca(2+) and Na(+), L-type Ca(2+), and large conductance Ca(2+)-activated K(+) channels. The nine variants are tested in turn, and model fits suggest that stress control of Ca(2+) or Na(+) influx through NSC, supplementary Ca(2+) or Na(+), or L-type Ca(2+) channels is sufficient to produce observed steady-state diameter changes with pressure. However, simulations of steady-state VSM membrane potential, cytosolic Ca(2+), and Na(+) with pressure show only that Na(+) influx through NSC channel also generates known trends with increasing pressure, indicating that stress-controlled Na(+) influx through NSC is sufficient to generate the myogenic response.
authors.affiliation: Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53213, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Carlson
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Beard
mesh_terms: D000818:Animals; D001160:Arterioles / Q000378:metabolism; D001794:Blood Pressure; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D003198:Computer Simulation; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism*; D007700:Kinetics; D040542:Mechanotransduction, Cellular; D008564:Membrane Potentials; D008643:Mesentery / Q000098:blood supply; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism; D013314:Stress, Mechanical
chemical_list: D020746:Calcium Channels, L-Type; D007473:Ion Channels; D015222:Sodium Channels; C491711:nonselective cation channel protein, rat