Simulated microgravity alters rat mesenteric artery vasoconstrictor dynamics through an intracellular Ca²⁺release mechanism

Abstract

Colleran PN, Behnke BJ, Wilkerson MK, Donato AJ, Delp MD. Simulated microgravity alters rat mesenteric artery vasoconstrictor dynamics through an intracellular Ca 2ϩ release mechanism. Am J Physiol Regul Integr Comp Physiol 294: R1577-R1585, 2008. First published March 19, 2008 doi:10.1152/ajpregu.00084.2008.-Previous work has shown that orthostatic hypotension associated with cardiovascular deconditioning results from inadequate peripheral vasoconstriction. We used the hindlimb-unloaded (HU) rat in this study as a model to induce cardiovascular deconditioning. The purpose of this study was to test the hypothesis that 14 days of HU diminishes vasoconstrictor responsiveness of mesenteric resistance arteries. Mesenteric resistance arteries from control (n ϭ 43) and HU (n ϭ 44) rats were isolated, cannulated, and pressurized to 108 cm H2O for in vitro experimentation. Myogenic (intralumenal pressure ranging from 30 to 180 cm H2O), KCl (2-100 mM), norepinephrine (NE, 10 Ϫ9 -10 Ϫ4 M) and caffeine (1-20 mM) induced vasoconstriction, as well as the temporal dynamics of vasoconstriction to NE, were determined. The active myogenic and passive pressure responses were unaltered by HU when pressures remained within physiological range. However, vasoconstrictor responses to KCl, NE, and caffeine were diminished by HU, as well as the rate of constriction to NE (C, 14.8 Ϯ 3.6 m/s vs. HU 7.6 Ϯ 1.8 m/s). Expression of sarcoplasmic reticulum Ca 2ϩ ATPase 2 and ryanodine 3 receptor mRNA was unaffected by HU, while ryanodine 2 receptor mRNA and protein expression were diminished in mesenteric arteries from HU rats. These data suggest that HU-induced and microgravity-associated orthostatic intolerance may be due, in part, to an attenuated vasoconstrictor responsiveness of mesenteric resistance arteries resulting from a diminished ryanodine 2 receptor Ca 2ϩ release mechanism.hindlimb unloading; vasoconstrictor responsiveness FOLLOWING EXPOSURE TO WEIGHTLESSNESs, many astronauts experience postflight orthostatic hypotension (6, 52) due, in part, to a diminished ability of the cardiovascular system to rapidly elevate peripheral vascular resistance (PVR) (1,2,8,36,52,53). It has been proposed that the diminished ability to elevate PVR following spaceflight may result from altered function of the afferent limb of the baroreceptors, central integration, sympathetic efferents, or end-organ responsiveness to sympathetic stimulation (8). Evidence for end-organ (vascular) hyporesponsiveness has been provided by Whitson et al. (54) and Levine et al. (27), who reported no difference in preflight vs. postflight PVR during orthostasis despite higher postflight levels of plasma catecholamine concentration and muscle sympathetic nerve activity. Similar reductions in vasoconstrictor responsiveness have been reported by investigators using prolonged bedrest (44, 46). Therefore, evidence suggests endorgan responsiveness to vasoconstrictor stimuli is diminished in humans following microgravity and bedrest deconditioning.In addition, orthostatic intol...

Up-regulation of ryanodine receptor expression increases the calcium-induced calcium release and spontaneous calcium signals in cerebral arteries from hindlimb unloaded rats

“…The increase in RyR1 expression and function in VSMC of HU rats fits with the different effects measured previously and provides a new insight complementary to the increase in Ltype Ca 2+ current density and membrane VDCC α 1C subunit expression described in cerebral VSMC after HU [51]. RyR1 appears to be a major target of vascular adaptation to HU and the regulation of its expression depends on the effects of HU on the intravascular blood loading [7,12,28]. If the cellular sensor of gravity is not yet described, the modulation of RyR1 expression was described before not only in VSMC but also in skeletal muscle [3].…”

“…The vascular adaptation to μG likely involves a response of factors known to regulate blood pressure, including: (1) control of plasma volume [37]; (2) modulation of baro-and cardiopulmonary reflexes inducing the decrease of cardiac function [19]; and finally (3) adaptation of intrinsic properties of vascular endothelial and smooth muscle cells (VSMC). We have focused our study on this last factor and used the hindlimb unloaded (HU) rat model as it simulates the biological effects of μG; especially, modulations of vascular reactivity were described in this model [7,28,39,53]. Vascular reactivity and tone are regulated by complex Ca 2+ signals.…”

Differential Regulation and Recovery of Intracellular Ca2+ in Cerebral and Small Mesenteric Arterial Smooth Muscle Cells of Simulated Microgravity Rat

“…In contrast, there is a report that 14-day hindlimb unloading decreased the level of intracellular Ca 2+ in rat small mesenteric VSMCs by reducing the function of ryanodine-sensitive Ca 2+ releases associated with the downregulation of RyR2 mRNA and protein expression [18]. We also reported that 28-day simulated microgravity down-regulated the Ca L channels in rat small mesenteric VSMCs [17].…”

Low-magnitude whole body vibration with resistive exercise as a countermeasure against cardiovascular deconditioning after 60 days of head-down bed rest

“…In humans, impairments of macro-and microcirculation are also involved in this downregulation (1). On rodent models, studies were carried out and showed that simulated weightlessness has negative effects on structural (13) and functional properties (8,14) of vasculature. Another part of this downregulation is an alteration of equilibrium system (40).…”