Hindlimb unweighting decreases ecNOS  gene expression and endothelium-dependent  dilation in rat soleus feed arteries

Jasperse, Jeffrey L.; Woodman, Christopher R.; Price, Elmer M.; Hasser, Eileen M.; Laughlin, M. Harold

doi:10.1152/jappl.1999.87.4.1476

Cited by 58 publications

(94 citation statements)

References 36 publications

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“…soleus muscle blood flow induced by hindlimb unweighting are associated with reductions in eNOS expression and ACh-induced dilation in SFA (15,18). Although previous studies to determine the effect of aging on skeletal muscle blood flow did not reveal age-related decrements in resting blood flow to the rat hindlimb (9,13), the effect of aging on intraluminal shear stress within SFA is not known.…”

Section: Discussionmentioning

confidence: 91%

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

Woodman

Price

Laughlin

2002

Journal of Applied Physiology

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105

123

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. Aging induces muscle-specific impairment of endothelium-dependent dilation in skeletal muscle feed arteries. J Appl Physiol 93: 1685-1690, 2002; 10.1152/ japplphysiol.00461.2002.-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 Ϯ 0.04 vs. 0.8 Ϯ 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 (Ϫ71 and Ϫ54%, 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. endothelial nitric oxide synthase; superoxide dismutase; nitric oxide; acetylcholine; sodium nitroprusside RESULTS FROM SEVERAL STUDIES indicate that endothelial function in conduit arteries declines with age in humans and animals (3,4,7,8,10,11,16,23). The endothelial dysfunction induced by aging is characterized by blunted vasodilator responses of conduit arteries to select endothelium-dependent agonists (3,4,7,8,10,11,16,23). The mechanism(s) for the detrimental effects of age on endothelium-dependent dilation is not fully understood; however, age-associated decrements in the ability of endothelial cells to produce and/or release nitric oxide (NO) may contribute to the dysfunction (3,11,16). This speculation is supported by experimental evidence indicating that vasodilation in response to ACh and bradykinin is impaired in aorta from senescent subjects, whereas dilation to sodium nitroprusside (SNP) is not compromised (3,5,16).An age-associated decline in the expression of endothelial NO synthase (eNOS), decreasing local production of NO, is one mechanism that may contribute to impaired endothelium-mediated dilation in conduit arteries of senescent animals. Indeed, age-related reductions eNOS mRNA expression have been reported in aorta of senescent rats (3, 6). Alternatively, decreased expression of Cu/Zn-dependent superoxide dismutase (SOD-1) may contribute to impaired endothelium-mediated dilation by compromising the ability to scavenge superoxide anion (O 2 Ϫ ⅐), decreasing the bio...

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Section: Discussionmentioning

confidence: 91%

“…Differences in eNOS and SOD-1 protein expression were assessed in single feed arteries (matched for diameter and length) by using immunoblot analysis as described previously in detail (15,28). eNOS protein expression was evaluated with a monoclonal antibody (1:1,600; catalog no.…”

Section: Quantification Of Enos and Sod-1 Expressionmentioning

confidence: 99%

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

Woodman

Price

Laughlin

2002

Journal of Applied Physiology

Self Cite

105

123

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“…Data on the effect of inactivity are controversial. Previous animal studies (23,40,51) mimicking physical inactivity by hindlimb unloading report inconsistent results with some studies showing a decreased nitric oxide synthase (NOS) gene expression and concomitant attenuated endothelium-dependent vasodilator responses, whereas other studies (38,50) report an upregulation of the NOS system. In humans, a recent bed-rest study demonstrated that plasma nitrate and nitrite concentration, an indicator of endogenous NO production, was decreased after 14 days of bed-rest immobilization (25).…”

Section: Discussionmentioning

confidence: 99%

Preserved flow-mediated dilation in the inactive legs of spinal cord-injured individuals

Groot¹,

Poelkens²,

Kooijman³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

105

110

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.-The aim of the study was to assess endothelial function, measured by flow-mediated dilation (FMD), in an inactive extremity (leg) and chronically active extremity (arm) within one subject. Eleven male spinal cord-injured (SCI) individuals and eleven male controls (C) were included. Echo Doppler measurements were performed to measure FMD responses after 10 and 5 min of arterial occlusion of the leg (superficial femoral artery, SFA) and the arm (brachial artery, BA), respectively. A nitroglycerine spray was administered to determine the endothelium independent vasodilatation in the SFA. In the SFA, relative changes in FMD were significantly enhanced in SCI compared with C (SCI: 14.1 Ϯ 1.3%; C: 9.2 Ϯ 2.3%), whereas no differences were found in the BA (SCI: 12.5 Ϯ 2.9%; C: 14.2 Ϯ 3.3%). Because the FMD response is directly proportional to the magnitude of the stimulus, the FMD response was also expressed relative to the shear rate. No differences between the groups were found for the FMD-to-shear rate ratio in the SFA (SCI:0.061 Ϯ 0.023%/s Ϫ1 ; C: 0.049 Ϯ 0.024%/s Ϫ1 ), whereas the FMD-to-shear rate ratio was significantly decreased in the BA of SCI individuals (SCI: 0.037 Ϯ 0.01%/s Ϫ1 ; C: 0.061 Ϯ 0.027%/s Ϫ1 ). The relative dilatory response to nitroglycerine did not differ between the groups. (SCI: 15.6 Ϯ 2.0%; C: 13.4 Ϯ 2.3%). In conclusion, our results indicate that SCI individuals have a preserved endothelial function in the inactive legs and possibly an attenuated endothelial function in the active arms compared with controls. vascular endothelial function; deconditioning; ultrasound THE ENDOTHELIUM plays an essential role in vascular homeostasis and is able to respond to physical and chemical stimuli by the synthesis and release of vasoactive, thromboregulatory, and growth factor substances (37). Impaired endothelial function has been suggested as a key early event in the development of atherosclerosis, and a high correlation between endothelial dysfunction and risk factors for cardiovascular diseases, including hypertension, hypercholesterolemia, cigarette smoking, diabetes, and aging, has been reported (6 -8, 12, 29, 33, 47, 48). Besides the above-mentioned traditional risk factors, it is well known that physical inactivity is associated with an increased risk of developing cardiovascular diseases (32). However, at present, the relationship between inactivity and endothelial dysfunction is not clear. In individuals with paraplegia, the part of the body below the lesion level is paralyzed and thus extremely inactive (20,39). In contrast, the upper limbs are often relatively active because the arms are used for ambulation due to their wheelchair-bound life-style (43). A spinal cord injury (SCI), therefore, offers a unique "human model of nature" to assess peripheral vascular adaptations to inactivity (legs) and activity (arms) on endothelial function within one subject.Healthy vessels are capable of accommodating to an increase in blood flow by dilating the internal vessel diameter, a phenomenon called fl...

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“…To determine whether the decreased NOS signaling is related to diminished expression of endothelial NOS (eNOS) or superoxide dismutase (SOD), relative differences in eNOS and SOD-1 protein content were assessed in gastrocnemius first-order arterioles by Western blot as described previously (31). eNOS protein content was evaluated with a monoclonal antibody (1:1,600; catalog no.…”

Section: Study 3: Endothelium-dependent and -Independent Vasodilationmentioning

confidence: 99%

Decreased NO signaling leads to enhanced vasoconstrictor responsiveness in skeletal muscle arterioles of the ZDF rat prior to overt diabetes and hypertension

Lesniewski¹,

Donato²,

Behnke³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Approximately 40% of patients with type 2 diabetes present with concurrent hypertension at the time of diabetes diagnosis. Increases in peripheral vascular resistance and correspondingly enhanced vasoconstrictor capacity could have profound implications for the development of hypertension and the progression of insulin resistance to overt diabetes. The purpose of this study was to determine whether skeletal muscle arteriolar vasoconstrictor dysfunction precedes or occurs concurrently with the onset of diabetes and hypertension. Male Zucker diabetic fatty (ZDF) rats were studied at 7, 13, and 20 wk of age to represent prediabetic and short-term and long-term diabetic states, respectively. Conscious mean arterial pressure (MAP), fasted plasma insulin and glucose, vasoconstrictor responses, and passive mechanical properties of isolated skeletal muscle arterioles were measured in prediabetic, diabetic, and age-matched control rats. Elevated MAP was manifest in short-term diabetes (control 117 ± 1, diabetic 135 ± 3 mmHg) and persisted with long-term diabetes (control 113 ± 2, diabetic 135 ± 3 mmHg). This higher MAP was preceded by augmented arteriolar vasoconstrictor responses to norepinephrine and endothelin-1 and followed by diminished β-adrenergic vasodilation and enhanced myogenic constriction in long-term diabetes. Furthermore, we demonstrate that diminished nitric oxide (NO) signaling underlies the increases in vasoconstrictor responsiveness in arterioles from prediabetic and diabetic rats. Arteriolar stiffness was not different between control and prediabetic or diabetic rats at any time point studied. Collectively, these results indicate that increases in vasoconstrictor responsiveness resulting from diminished NO signaling in skeletal muscle arterioles precede the development of diabetes and hypertension in ZDF rats. Keywordstype 2 diabetes; vasoconstriction; nitric oxide; norepinephrine; endothelin-1 Diabetes Mellitus Affects approximately 16 million Americans (15,29), and the cardiovascular complications associated with the disease are the leading cause of the morbidity and mortality Address for reprint requests and other correspondence: M. D. Delp, Dept. of Applied Physiology and Kinesiology, 100 FLG, Univ. of Florida, Gainesville, FL 32611 (e-mail: mdelp@ufl.edu). NIH Public Access Author ManuscriptAm J Physiol Heart Circ Physiol. Author manuscript; available in PMC 2009 April 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript among patients (1). The presence of diabetes increases cardiovascular disease risk two-to sixfold over that of normal healthy adults (2,5,27,30), with 40% of type 2 diabetic patients presenting with concurrent hypertension at the time of diagnosis (54). This early onset of hypertension suggests that cardiovascular complications may precede the onset of overt diabetes and result from a long-term impaired glucose tolerance and hyperinsulinemia (28). Alterations in vasoconstrictor responses during this prediabetic state may have profound implications...

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Hindlimb unweighting decreases ecNOS gene expression and endothelium-dependent dilation in rat soleus feed arteries

Cited by 58 publications

References 36 publications

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

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

Preserved flow-mediated dilation in the inactive legs of spinal cord-injured individuals

Decreased NO signaling leads to enhanced vasoconstrictor responsiveness in skeletal muscle arterioles of the ZDF rat prior to overt diabetes and hypertension

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