Hindlimb unweighting induces changes in the RhoA-Rho-kinase pathway of the rat abdominal aorta

Summers, Scott M.; Nguyen, Steven Vu; Purdy, Ralph E.

doi:10.1016/j.vph.2008.03.006

Cited by 9 publications

(10 citation statements)

References 31 publications

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“…Thus the mechanisms underlying the HLU-induced vasoconstrictor hyporesponsiveness in this vessel are unknown. In a previous study (29), we demonstrated that HLU impaired RhoA/Rho kinase signaling in the abdominal aorta, leading to a decreased capacity for vasoconstrictormediated myosin light-chain phosphorylation. We hypothesized that this biochemical change contributed to the HLUinduced vasoconstrictor hyporesponsiveness.…”

mentioning

confidence: 79%

Hindlimb unweighting induces changes in the p38^MAPKcontractile pathway of the rat abdominal aorta

Summers

Hayashi²,

Nguyen³

et al. 2009

Journal of Applied Physiology

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Hindlimb unweighting (HLU) of rats is a model used to mimic the cephalic fluid shift potentially involved in the orthostatic intolerance experienced by astronauts. Certain arteries in these rats exhibit a decreased contractile response to adrenergic agonists. It was shown previously that this may be caused by changes in thick filament regulation (Summers et al., Vascul Pharmacol 48: 208-214, 2008). In the present study, it was hypothesized that HLU also modifies thin filament regulation by effects on p38(MAPK) and ERK. Abdominal aorta rings from 20-day HLU rats and untreated controls were subjected to phenylephrine and phorbol 12,13-dibutyrate (PDBU) concentration response curves in the presence and absence of two inhibitors: the p38(MAPK) inhibitor SB-203580 and the MEK inhibitor U-0126. SB-203580 decreased control sensitivity to both agonists, but HLU sensitivity was not significantly affected. U-0126, which blocks enzymes immediately upstream of ERK, affected sensitivity to both agonists equally between control and HLU. Western blot analysis revealed no change in total levels of p38(MAPK) and its downstream target heat shock protein 27 but did reveal a decrease in phosphorylated levels of both after stimulation with PDBU and phenylephrine after HLU treatment. Neither total ERK nor phosphorylated levels after stimulation were affected by HLU. Total levels of caldesmon, a molecule downstream of both pathways, were decreased, but phosphorylated levels after stimulation were decreased by roughly twice as much. The results of this study demonstrate that HLU downregulates p38(MAPK), but not ERK, signaling. In turn, this may decrease actin availability for contraction.

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mentioning

confidence: 79%

Hindlimb unweighting induces changes in the p38^MAPKcontractile pathway of the rat abdominal aorta

Summers

Hayashi²,

Nguyen³

et al. 2009

Journal of Applied Physiology

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“…However, in another study [27], decreased effect of RhoA/ROCK pathway was shown to be contributing to 20-day HU-induced decreased abdominal aortic vasoconstriction. Interestingly, previous studies [10,18,24] have consistently confirmed decreased responsiveness of both femoral artery and abdominal aorta in HU rats.…”

Section: Introductionmentioning

confidence: 89%

“…Then rings were incubated for 1 h with 3 μM Y-27632, a ROCK inhibitor, after which the dose-dependent contraction stimulated by PE or KCl was elicited again. The concentration of Y-27632 applied in this experiment was chosen according to the preliminary experiments and the work by Uehata et al [30] and Summers et al [27]. 50 % effective concentration (EC 50 ) was calculated to evaluate sensitivity of artery rings to vasoactive substances.…”

Section: Isometric Force Measurementmentioning

confidence: 99%

“…As currently well accepted [4,10,14,26,27], the contraction of vascular smooth muscle cells (VSMCs) is mainly determined by the phosphorylation/ dephosphorylation of myosin light chain (MLC), which is regulated by the balance between myosin light chain kinase (MLCK) and myosin light chain phosphotase (MLCP). In brief, a rise in cytosolic Ca 2+ concentration produces VSMCs contraction by activation of Ca 2+ -calmodulin-activated MLCK and subsequently phosphorylation of MLC, whereas activation of Ca 2+ -independent MLCP could induce dephosphorylation of MLC and inhibit contraction.…”

Section: Introductionmentioning

confidence: 99%

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28-Day hindlimb unweighting reduces expression of Rho kinase and inhibits its effects in femoral artery of rat

et al. 2015

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Previous studies have demonstrated inconsistent roles of Rho kinase (ROCK) in the decreased vasoconstriction of rat hindquarter vessels induced by hindlimb unweighting (HU). The present study was designed to determine the unclear role of ROCK in the mediation of HU-induced decreased femoral arterial vasoconstriction. 28-day HU rat was adopted as the animal model. With or without Y-27632, a ROCK inhibitor, isometric force of femoral artery was measured. The expression of ROCK and its effects on downstream targets were also examined. Results showed that (1) HU caused a significant decrease of the phenylephrine (PE)-evoked and potassium chloride (KCl)-evoked femoral arterial vasoconstriction (P < 0.05), confirming the functional findings by previous studies. (2) Inhibition of ROCK with Y-27632 produced an equal reduction of the vasoconstriction in CON and HU. (3) HU significantly decreased ROCK II expression and the effects of ROCK on myosin light-chain phosphatase (MLCP) and MLC (P < 0.05), but increased p65 nuclear translocation (P < 0.05) and inducible nitric oxide synthase (iNOS) expression (P < 0.05). (4) HU significantly (P < 0.05) increased NO production in femoral arteries, with Y-27632 significantly (P < 0.01) amplifying this effect. These findings have revealed that 28-day HU reduced the expression and effects of ROCK on downstream targets both directly (MLCP and MLC) and possibly indirectly (NF-κB/iNOS/NO pathway) related to vasoconstriction in femoral arteries.

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“…The model of hindlimb unloading, originally developed by Ilin and Novikov (1980) and popularized by Morey-Holton (Morey-Holton and Globus, 2002), has been repeatedly applied to on-ground studies of cardiovascular adaptation to microgravity. The hindlimb-unloaded rats and mice display vascular remodeling (Behnke et al, 2008;De Salvatore et al, 2004;Summers et al, 2008), hematological changes (Dunn et al, 1985;Ryou, 2012) and alterations of blood pressure and/or heart rate (Powers and Bernstein, 2004;Tarasova et al, 2001;Tsvirkun et al, 2012;Zhang et al, 2008), along with other signs of cardiovascular adaptation (Bouzeghrane et al, 1996;Brizzee and Walker, 1990;Chew and Segal, 1997;Fagette et al, 1995;Moffitt et al, 1998). In relation to fluid shifts, the increase of hydrostatic pressure in the neck tissues (Hargens et al, 1984) and intracranial pressure was reported in hindlimb-unloaded rats (Krasnov et al, 2005;Maurel et al, 1996), although measurement of blood and interstitial fluid volumes produced ambiguous data (Bouzeghrane et al, 1996;Chew and Segal, 1997;Deever et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Fluid shift vs. body size: changes of hematological parameters and body fluid volumes in hindlimb-unloaded mice, rats and rabbits

Andreev-Andrievskiy

Popova

Lagereva

et al. 2018

Journal of Experimental Biology

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The cardiovascular system is adapted to gravity, and reactions to the loss of gravity in space are presumably dependent on body size. The dependence of hematological parameters and body fluid volume on simulated microgravity have never been studied as an allometric function before. Thus, we estimated red blood cell (RBC), blood and extracellular fluid volume in hindlimb-unloaded (HLU) or control (attached) mice, rats and rabbits. RBC decrease was found to be size independent, and the allometric dependency for RBC loss in HLU and control animals shared a common power (-0.054±0.008) but a different coefficient (8.66±0.40 and 10.73±0.49, respectively,<0.05). Blood volume in HLU animals was unchanged compared with that of controls, disregarding body size. The allometric dependency of interstitial fluid volume in HLU and control mice shared (1.02±0.09) but had different powers (0.708±0.017 and 0.648±0.016, respectively, <0.05), indicating that the interstitial fluid volume increase during hindlimb unloading is more pronounced in larger animals. Our data underscore the importance of size-independent mechanisms of cardiovascular adaptation to weightlessness. Despite the fact that the use of mice hampers application of a straightforward translational approach, this species is useful for gravitational biology as a tool to investigate size-independent mechanisms of mammalian adaptation to microgravity.

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Hindlimb unweighting induces changes in the RhoA-Rho-kinase pathway of the rat abdominal aorta

Cited by 9 publications

References 31 publications

Hindlimb unweighting induces changes in the p38^MAPKcontractile pathway of the rat abdominal aorta

Hindlimb unweighting induces changes in the p38^MAPKcontractile pathway of the rat abdominal aorta

28-Day hindlimb unweighting reduces expression of Rho kinase and inhibits its effects in femoral artery of rat

Fluid shift vs. body size: changes of hematological parameters and body fluid volumes in hindlimb-unloaded mice, rats and rabbits

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Hindlimb unweighting induces changes in the RhoA-Rho-kinase pathway of the rat abdominal aorta

Cited by 9 publications

References 31 publications

Hindlimb unweighting induces changes in the p38MAPKcontractile pathway of the rat abdominal aorta

Hindlimb unweighting induces changes in the p38MAPKcontractile pathway of the rat abdominal aorta

28-Day hindlimb unweighting reduces expression of Rho kinase and inhibits its effects in femoral artery of rat

Fluid shift vs. body size: changes of hematological parameters and body fluid volumes in hindlimb-unloaded mice, rats and rabbits

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Hindlimb unweighting induces changes in the p38^MAPKcontractile pathway of the rat abdominal aorta

Hindlimb unweighting induces changes in the p38^MAPKcontractile pathway of the rat abdominal aorta