Short-term increases in pressure and shear stress attenuate age-related declines in endothelial function in skeletal muscle feed arteries

Although advancing age is often associated with attenuated skeletal muscle blood flow and skeletal muscle feed arteries (SMFAs) have been recognized to play a regulatory role in the vasculature, little is known about the impact of age on the vasodilatory capacity of human SMFAs. Therefore, endothelium-dependent and -independent vasodilation were assessed in SMFAs (diameter: 544 ± 63 μm) obtained from 24 (equally represented) young (33 ± 2 yr) and old (71 ± 2 yr) subjects in response to three stimuli: 1) flow-induced shear stress, 2) ACh, and 3) sodium nitropusside (SNP). Both assessments of endothelium-dependent vasodilation, flow (young subjects: 68 ± 1% and old subjects: 32 ± 7%) and ACh (young subjects: 92 ± 3% and old subjects: 73 ± 4%), were significantly blunted ( P < 0.05) in SMFAs of old compared with young subjects, with no such age-related differences in endothelium-independent vasodilation (SNP). In response to an increase in flow-induced shear stress, vasodilation kinetics (time constant to reach 63% of the amplitude of the response: 55 ± 1 s in young subjects and 92 ± 7 s in old subjects) and endothelial nitric oxide synthase (eNOS) activation (phospho-eNOSs1177/total eNOS: 1.0 ± 0.1 in young subjects and 0.2 ± 0.1 in old subjects) were also significantly attenuated in old compared with young subjects ( P < 0.05). Furthermore, the vessel superoxide concentration was greater in old subjects (old subjects: 3.9 ± 1.0 area under curve/mg and young subjects: 1.7 ± 0.1 area under the curve/mg, P < 0.05). These findings reveal that the endothelium-dependent vasodilatory capacity, including vasodilation kinetics but not smooth muscle function, of human SMFAs is blunted with age and may be due to free radicals. Given the potential regulatory role of SMFAs in skeletal muscle blood flow, these findings may explain, at least in part, the often observed attenuated perfusion of skeletal muscle with advancing age that may contribute to exercise intolerance in the elderly.

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Short-term increases in intraluminal pressure reverse age-related decrements in endothelium-dependent dilation in soleus muscle feed arteries

Journal of Applied Physiology ◽

10.1152/japplphysiol.00416.2007 ◽

2007 ◽

Vol 103 (4) ◽

pp. 1172-1179 ◽

Cited By ~ 17

Author(s):

Christopher R. Woodman ◽

Daniel W. Trott ◽

M. Harold Laughlin

Keyword(s):

Protein Content ◽

Soleus Muscle ◽

Intraluminal Pressure ◽

Separate Experiment ◽

Enos Expression ◽

Short Term ◽

Age Related ◽

Enos Mrna ◽

Feed Arteries ◽

Increased Pressure

We tested the hypothesis that short-term increases in intraluminal pressure improve endothelium-dependent dilation and increase endothelial nitric oxide (NO) synthase (eNOS) expression in senescent soleus muscle feed arteries (SFA). SFA isolated from young (4 mo) and old (24 mo) Fischer 344 rats were cannulated and pressurized at 90 (p90) or 130 (p130) cmH2O for 4 h. At the end of the 4-h protocol, pressure in p130 SFA was lowered to 90 cmH2O for examination of endothelium-dependent (flow- or ACh-induced) vasodilation. Flow- and ACh-induced dilations were blunted in old p90 SFA relative to young p90 SFA. Pretreatment with increased pressure (p130) improved flow- and ACh-induced dilations in old SFA, such that vasodilator responses were similar to those in young SFA. In the presence of Nω-nitro-l-arginine (l-NNA) or l-NNA + indomethacin (Indo), flow-induced dilation was inhibited in old p130 SFA, such that the response was not greater than the response in old p90 SFA. In old p130 SFA, ACh-induced dilation was inhibited by l-NNA + Indo (not l-NNA alone). In a separate experiment, SFA were pressurized at 70, 90, 110, or 130 cmH2O for 4 h, and eNOS mRNA and protein content were assessed. Increased pressure induced eNOS mRNA expression in young (not old) SFA. eNOS protein content was not altered in young or old SFA. These results indicate that short-term increases in intraluminal pressure improve endothelium-dependent dilation in senescent SFA, in part by enhancing NO bioavailability; however, the beneficial effect was not associated with increased eNOS expression.

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Aging induces muscle-specific impairment of endothelium-dependent dilation in skeletal muscle feed arteries

Journal of Applied Physiology ◽

10.1152/japplphysiol.00461.2002 ◽

2002 ◽

Vol 93 (5) ◽

pp. 1685-1690 ◽

Cited By ~ 79

Author(s):

Christopher R. Woodman ◽

Elmer M. Price ◽

M. Harold Laughlin

Keyword(s):

Skeletal Muscle ◽

Mrna Expression ◽

Vascular Function ◽

Fischer 344 ◽

Old Rats ◽

The Right ◽

Oxide Synthase ◽

Endothelial Nitric Oxide ◽

Feed Arteries ◽

Skeletal Muscle Feed Arteries

We tested the hypothesis that aging decreases endothelium-dependent vasodilation in feed arteries perfusing rat skeletal muscle. In addition, we tested the hypothesis that attenuated vasodilator responses are associated with decreased endothelial nitric oxide synthase (eNOS) and superoxide dismutase-1 (SOD-1) expression. Soleus feed arteries (SFA) and gastrocnemius feed arteries (GFA) were isolated from young (4 mo) and old (24 mo) male Fischer 344 rats. Feed arteries from the right hindlimb were cannulated with two glass micropipettes for examination of endothelium-dependent [acetylcholine (ACh)] and endothelium-independent [adenosine (Ado) or sodium nitroprusside (SNP)] vasodilator function. Feed arteries from the left hindlimb were frozen and used to assess eNOS and SOD-1 protein and mRNA expression. In SFA, endothelium-dependent dilation to ACh was reduced in old rats (0.9 ± 0.04 vs. 0.8 ± 0.03), whereas dilator responses to Ado and SNP were similar in SFA of young and old rats. In GFA, vasodilator responses to ACh, Ado, and SNP were not altered by age. eNOS and SOD-1 protein expression declined with age in SFA (−71 and −54%, respectively) but not in GFA. eNOS and SOD-1 mRNA expression were not altered by age in SFA or GFA. Collectively, these data indicate aging induces muscle-specific impairment of endothelium-dependent vascular function in SFA.

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Transcriptome-wide RNA sequencing analysis of rat skeletal muscle feed arteries. I. Impact of obesity

Journal of Applied Physiology ◽

10.1152/japplphysiol.01233.2013 ◽

2014 ◽

Vol 116 (8) ◽

pp. 1017-1032 ◽

Cited By ~ 19

Author(s):

Nathan T. Jenkins ◽

Jaume Padilla ◽

Pamela K. Thorne ◽

Jeffrey S. Martin ◽

R. Scott Rector ◽

...

Keyword(s):

Skeletal Muscle ◽

Endothelial Cell ◽

Rna Sequencing ◽

Differentially Expressed ◽

Aortic Endothelial Cell ◽

Oletf Rats ◽

Long Evans ◽

Feed Arteries ◽

Skeletal Muscle Feed Arteries ◽

Aortic Endothelial

We employed next-generation RNA sequencing (RNA-Seq) technology to determine the influence of obesity on global gene expression in skeletal muscle feed arteries. Transcriptional profiles of the gastrocnemius and soleus muscle feed arteries (GFA and SFA, respectively) and aortic endothelial cell-enriched samples from obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats were examined. Obesity produced 282 upregulated and 133 downregulated genes in SFA and 163 upregulated and 77 downregulated genes in GFA [false discovery rate (FDR) < 10%] with an overlap of 93 genes between the arteries. In LETO rats, there were 89 upregulated and 114 downregulated genes in the GFA compared with the SFA. There were 244 upregulated and 275 downregulated genes in OLETF rats (FDR < 10%) in the GFA compared with the SFA, with an overlap of 76 differentially expressed genes common to both LETO and OLETF rats in both the GFA and SFA. A total of 396 transcripts were found to be differentially expressed between LETO and OLETF in aortic endothelial cell-enriched samples. Overall, we found 1) the existence of heterogeneity in the transcriptional profile of the SFA and GFA within healthy LETO rats, 2) that this between-vessel heterogeneity was markedly exacerbated in the hyperphagic, obese OLETF rat, and 3) a greater number of genes whose expression was altered by obesity in the SFA compared with the GFA. Also, results indicate that in OLETF rats the GFA takes on a relatively more proatherogenic phenotype compared with the SFA.

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Vasodilatory function in human skeletal muscle feed arteries with advancing age: the role of adropin

The Journal of Physiology ◽

10.1113/jp277410 ◽

2019 ◽

Vol 597 (7) ◽

pp. 1791-1804 ◽

Cited By ~ 4

Author(s):

Oh Sung Kwon ◽

Robert H. I. Andtbacka ◽

John R. Hyngstrom ◽

Russell S. Richardson

Keyword(s):

Skeletal Muscle ◽

Human Skeletal Muscle ◽

Vasodilatory Function ◽

Feed Arteries ◽

Skeletal Muscle Feed Arteries

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The Role of TRPV Ion Channels in Heat-induced Sympatholysis of Human Skeletal Muscle Feed Arteries

Medicine & Science in Sports & Exercise ◽

10.1249/01.mss.0000494172.87916.81 ◽

2014 ◽

Vol 46 ◽

pp. 328-329

Author(s):

Jayson R. Gifford ◽

Stephen J. Ives ◽

Song Y. Park ◽

Robert H.I. Andtbacka ◽

Joel D. Trinity ◽

...

Keyword(s):

Skeletal Muscle ◽

Ion Channels ◽

Human Skeletal Muscle ◽

Feed Arteries ◽

Skeletal Muscle Feed Arteries

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Skeletal muscle atrophy during short-term disuse: Implications for age-related sarcopenia

Ageing Research Reviews ◽

10.1016/j.arr.2013.07.003 ◽

2013 ◽

Vol 12 (4) ◽

pp. 898-906 ◽

Cited By ~ 158

Author(s):

Benjamin T. Wall ◽

Marlou L. Dirks ◽

Luc J.C. van Loon

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Skeletal Muscle Atrophy ◽

Short Term ◽

Age Related

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Heat and α1-adrenergic responsiveness in human skeletal muscle feed arteries: the role of nitric oxide

Journal of Applied Physiology ◽

10.1152/japplphysiol.00955.2012 ◽

2012 ◽

Vol 113 (11) ◽

pp. 1690-1698 ◽

Cited By ~ 19

Author(s):

Stephen J. Ives ◽

Robert H. I. Andtbacka ◽

Sun Hyung Kwon ◽

Yan-Ting Shiu ◽

Ting Ruan ◽

...

Keyword(s):

Nitric Oxide ◽

Skeletal Muscle ◽

Adrenergic Receptors ◽

Adrenergic Receptor ◽

Human Skeletal Muscle ◽

Bovine Endothelial Cells ◽

No Bioavailability ◽

Feed Arteries ◽

Skeletal Muscle Feed Arteries

Increased local temperature exerts a sympatholytic effect on human skeletal muscle feed arteries. We hypothesized that this attenuated α1-adrenergic receptor responsiveness may be due to a temperature-induced increase in nitric oxide (NO) bioavailability, thereby reducing the impact of the α1-adrenergic receptor agonist phenylephrine (PE). Thirteen human skeletal muscle feed arteries were harvested, and wire myography was used to generate PE concentration-response curves at 37°C and 39°C, with and without the NO synthase (NOS) inhibitor NG-monomethyl-l-arginine (l-NMMA). A subset of arteries ( n = 4) were exposed to 37°C or 39°C, and the protein content of endothelial NOS (eNOS) and α1-adrenergic receptors was determined by Western blot analysis. Additionally, cultured bovine endothelial cells were exposed to static or shear stress conditions at 37°C and 39°C and assayed for eNOS activation (phosphorylation at Ser1177), eNOS expression, and NO metabolites [nitrate + nitrite (NOx)]. Maximal PE-induced vasocontraction (PEmax) was lower at 39°C than at 37°C [39 ± 10 vs. 84 ± 30% maximal response to 100 mM KCl (KClmax)]. NO blockade restored vasocontraction at 39°C to that achieved at 37°C (80 ± 26% KClmax). Western blot analysis of the feed arteries revealed that heating increased eNOS protein, but not α1-adrenergic receptors. Heating of bovine endothelial cells resulted in greater shear stress-induced eNOS activation and NOx production. Together, these data reveal for the first time that, in human skeletal muscle feed arteries, NO blockade can restore the heat-attenuated α1-adrenergic receptor-mediated vasocontraction and implicate endothelium-derived NO bioavailability as a major contributor to heat-induced sympatholysis. Consequently, these findings highlight the important role of vasodilators in modulating the vascular response to vasoconstrictors.

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Transcriptome-wide RNA sequencing analysis of rat skeletal muscle feed arteries. II. Impact of exercise training in obesity

Journal of Applied Physiology ◽

10.1152/japplphysiol.01234.2013 ◽

2014 ◽

Vol 116 (8) ◽

pp. 1033-1047 ◽

Cited By ~ 19

Author(s):

Jaume Padilla ◽

Nathan T. Jenkins ◽

Pamela K. Thorne ◽

Jeffrey S. Martin ◽

R. Scott Rector ◽

...

Keyword(s):

Skeletal Muscle ◽

Endothelial Cells ◽

Exercise Training ◽

Training Program ◽

Rna Sequencing ◽

Gastrocnemius Muscle ◽

Aortic Endothelial Cells ◽

Feed Arteries ◽

Skeletal Muscle Feed Arteries ◽

Aortic Endothelial

We employed next-generation RNA sequencing (RNA-Seq) technology to determine the extent to which exercise training alters global gene expression in skeletal muscle feed arteries and aortic endothelial cells of obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Transcriptional profiles of the soleus and gastrocnemius muscle feed arteries (SFA and GFA, respectively) and aortic endothelial cell-enriched samples from rats that underwent an endurance exercise training program (EndEx; n = 12) or a interval sprint training program (IST; n = 12) or remained sedentary (Sed; n = 12) were examined. In response to EndEx, there were 39 upregulated (e.g., MANF) and 20 downregulated (e.g., ALOX15) genes in SFA and 1 upregulated (i.e., Wisp2) and 1 downregulated (i.e., Crem) gene in GFA [false discovery rate (FDR) < 10%]. In response to IST, there were 305 upregulated (e.g., MANF, HSPA12B) and 324 downregulated genes in SFA and 101 upregulated and 66 downregulated genes in GFA, with an overlap of 32 genes between arteries. Furthermore, in aortic endothelial cells, there were 183 upregulated (e.g., eNOS, SOD-3) and 141 downregulated (e.g., ATF3, Clec1b, npy, leptin) genes with EndEx and 71 upregulated and 69 downregulated genes with IST, with an overlap of 35 between exercise programs. Expression of only two genes (Tubb2b and Slc9a3r2) was altered (i.e., increased) by exercise in all three arteries. The finding that both EndEx and IST produced greater transcriptional changes in the SFA compared with the GFA is intriguing when considering the fact that treadmill bouts of exercise are associated with greater relative increases in blood flow to the gastrocnemius muscle compared with the soleus muscle.

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