Key points
In a rat model of ageing that is free of atherosclerosis or hypertension, E/A, a diagnostic measure of diastolic filling, decreases, and isovolumic relaxation time increases, indicating ...that both active and passive ventricular relaxation are impaired with advancing age.
Resting coronary blood flow and coronary functional hyperaemia are reduced with age, and endothelium‐dependent vasodilatation declines with age in coronary resistance arterioles.
Exercise training reverses age‐induced declines in diastolic and coronary microvascular function.
Thus, microvascular dysfunction and inadequate coronary perfusion are likely mechanisms of diastolic dysfunction in aged rats.
Exercise training, initiated at an advanced age, reverses age‐related diastolic and microvascular dysfunction; these data suggest that late‐life exercise training can be implemented to improve coronary perfusion and diastolic function in the elderly.
The risk for diastolic dysfunction increases with advancing age. Regular exercise training ameliorates age‐related diastolic dysfunction; however, the underlying mechanisms have not been identified. We investigated whether (1) microvascular dysfunction contributes to the development of age‐related diastolic dysfunction, and (2) initiation of late‐life exercise training reverses age‐related diastolic and microvascular dysfunction. Young and old rats underwent 10 weeks of exercise training or remained as sedentary, cage‐controls. Isovolumic relaxation time (IVRT), early diastolic filling (E/A), myocardial performance index (MPI) and aortic stiffness (pulse wave velocity; PWV) were evaluated before and after exercise training or cage confinement. Coronary blood flow and vasodilatory responses of coronary arterioles were evaluated in all groups at the end of training. In aged sedentary rats, compared to young sedentary rats, a 42% increase in IVRT, a 64% decrease in E/A, and increased aortic stiffness (PWV: 6.36 ± 0.47 vs.4.89 ± 0.41, OSED vs. YSED, P < 0.05) was accompanied by impaired coronary blood flow at rest and during exercise. Endothelium‐dependent vasodilatation was impaired in coronary arterioles from aged rats (maximal relaxation to bradykinin: 56.4 ± 5.1% vs. 75.3 ± 5.2%, OSED vs. YSED, P < 0.05). After exercise training, IVRT, a measure of active ventricular relaxation, did not differ between old and young rats. In old rats, exercise training reversed the reduction in E/A, reduced aortic stiffness, and eliminated impairment of coronary blood flow responses and endothelium‐dependent vasodilatation. Thus, age‐related diastolic and microvascular dysfunction are reversed by late‐life exercise training. The restorative effect of exercise training on coronary microvascular function may result from improved endothelial function.
Key points
In a rat model of ageing that is free of atherosclerosis or hypertension, E/A, a diagnostic measure of diastolic filling, decreases, and isovolumic relaxation time increases, indicating that both active and passive ventricular relaxation are impaired with advancing age.
Resting coronary blood flow and coronary functional hyperaemia are reduced with age, and endothelium‐dependent vasodilatation declines with age in coronary resistance arterioles.
Exercise training reverses age‐induced declines in diastolic and coronary microvascular function.
Thus, microvascular dysfunction and inadequate coronary perfusion are likely mechanisms of diastolic dysfunction in aged rats.
Exercise training, initiated at an advanced age, reverses age‐related diastolic and microvascular dysfunction; these data suggest that late‐life exercise training can be implemented to improve coronary perfusion and diastolic function in the elderly.
As multiple spacefaring nations contemplate extended manned missions to Mars and the Moon, health risks could be elevated as travel goes beyond the Earth's protective magnetosphere into the more ...intense deep space radiation environment. The primary purpose of this study was to determine whether mortality rates due to cardiovascular disease (CVD), cancer, accidents and all other causes of death differ in (1) astronauts who never flew orbital missions in space, (2) astronauts who flew only in low Earth orbit (LEO), and (3) Apollo lunar astronauts, the only humans to have traveled beyond Earth's magnetosphere. Results show there were no differences in CVD mortality rate between non-flight (9%) and LEO (11%) astronauts. However, the CVD mortality rate among Apollo lunar astronauts (43%) was 4-5 times higher than in non-flight and LEO astronauts. To test a possible mechanistic basis for these findings, a secondary purpose was to determine the long-term effects of simulated weightlessness and space-relevant total-body irradiation on vascular responsiveness in mice. The results demonstrate that space-relevant irradiation induces a sustained vascular endothelial cell dysfunction. Such impairment is known to lead to occlusive artery disease, and may be an important risk factor for CVD among astronauts exposed to deep space radiation.
Reduced availability of tetrahydrobiopterin (BH 4 ) contributes to the age-related decline of nitric oxide (NO)-mediated vasodilatation of soleus muscle arterioles. Depending
on availability of ...substrate and/or necessary co-factors, endothelial nitric oxide synthase (eNOS) can generate NO and/or
superoxide (O 2 â ). We evaluated the effects of age and chronic exercise on flow-induced vasodilatation and levels of NO and O 2 â in soleus muscle arterioles. Young (3 months) and old (22 months) male rats were exercise trained or remained sedentary (SED)
for 10 weeks. Flow-stimulated NO and O 2 â , as well as BH 4 and l -arginine content, were determined in soleus muscle arterioles. Flow-induced vasodilatation was assessed under control conditions
and during the blockade of O 2 â and/or hydrogen peroxide. Exercise training enhanced flow-induced vasodilatation in arterioles from young and old rats. Old
age reduced, and exercise training restored, BH 4 content and flow-stimulated NO availability. Flow-stimulated, eNOS-derived O 2 â levels were higher in arterioles from old SED compared to those from young SED rats. Exercise training increased flow-stimulated
eNOS-derived O 2 â levels in arterioles from young but not old rats. O 2 â scavenging with Tempol reduced flow-induced vasodilatation from all groups except young SED rats. Addition of catalase to
Tempol-treated arterioles eliminated flow-induced vasodilatation in arterioles from all groups. Catalase reduced flow-induced
vasodilatation from all groups. In Tempol-treated arterioles, flow-induced vasodilatation was restored by deferoxamine, an
iron chelator. These data indicate that uncoupling of eNOS contributes to the age-related decline in flow-induced vasodilatation;
however, reactive oxygen species are required for flow-induced vasodilatation in soleus muscle arterioles from young and old
rats.
Evidence indicates that cerebral blood flow is both increased and diminished in astronauts on return to Earth. Data from ground‐based animal models simulating the effects of microgravity have shown ...that decrements in cerebral perfusion are associated with enhanced vasoconstriction and structural remodeling of cerebral arteries. Based on these results, the purpose of this study was to test the hypothesis that 13 d of spaceflight Space Transportation System (STS)‐135 shuttle mission enhances myogenic vasoconstriction, increases medial wall thickness, and elicits no change in the mechanical properties of mouse cerebral arteries. Basilar and posterior communicating arteries (PCAs) were isolated from 9‐wk‐old female C57BL/6 mice for in vitro vascular and mechanical testing. Contrary to that hypothesized, myogenic vasoconstrictor responses were lower and vascular distensibility greater in arteries from spaceflight group (SF) mice (n=7) relative to ground‐based control group (GC) mice (n=12). Basilar artery maximal diameter was greater in SF mice (SF: 236±9 μm and GC: 215±5 μm) with no difference in medial wall thickness (SF: 12.4±1.6 μm; GC: 12.2±1.2 μm). Stiffness of the PCA, as characterized via nanoindentation, was lower in SF mice (SF: 3.4±0.3 N/m; GC: 5.4±0.8 N/m). Collectively, spaceflight‐induced reductions in myogenic vasoconstriction and stiffness and increases in maximal diameter of cerebral arteries signify that elevations in brain blood flow may occur during spaceflight. Such changes in cerebral vascular control of perfusion could contribute to increases in intracranial pressure and an associated impairment of visual acuity in astronauts during spaceflight.—Taylor, C. R., Hanna, M., Behnke, B. J., Stabley, J. N., McCullough, D. J., Davis III, R. T., Ghosh, P., Papadopoulos, A., Muller‐Delp, J. M., Delp, M. D. Spaceflight‐induced alterations in cerebral artery vasoconstrictor, mechanical, and structural properties: implications for elevated cerebral perfusion and intracranial pressure. FASEB J. 27, 2282–2292 (2013). www.fasebj.org
Ageing reduces endothelium-dependent vasodilatation through an endothelial nitric oxide synthase (NOS) signalling pathway.
The purpose of this study was to determine whether arginase activity ...diminishes endothelium-dependent vasodilatation in skeletal
muscle arterioles from old rats, and whether NOS substrate ( l -arginine) and cofactor (tetrahydrobiopterin; BH 4 ) concentrations are reduced. First-order arterioles were isolated from the soleus muscle of young (6 months old) and old
(24 months old) male Fischer 344 rats. In vitro changes in luminal diameter in response to stepwise increases in flow were determined in the presence of the NOS inhibitor
N G -nitro- l -arginine methyl ester ( l -NAME, 10 â5 mol l â1 ), the arginase inhibitor N Ï -hydroxy-nor- l -arginine (NOHA, 5 à 10 â4 mol l â1 ), exogenous l -arginine (3 à 10 â3 mol l â1 ) or the precursor for BH 4 synthesis sepiapterin (1 μmol l â1 ). Arteriolar l -arginine and BH 4 content were determined via HPLC. Ageing decreased flow-mediated vasodilatation by 52%, and this difference was abolished
with NOS inhibition. Neither inhibition of arginase activity nor addition of exogenous l -arginine had any effect on flow-mediated vasodilatation; arteriolar l -arginine content was also not different between age groups. BH 4 content was lower in arterioles from old rats (94 ± 8 fmol (mg tissue) â1 ) relative to controls (234 ± 21 fmol (mg tissue) â1 ), and sepiapterin elevated flow-mediated vasodilatation in arterioles from old rats. These results demonstrate that the impairment
of endothelium-dependent vasodilatation induced by old age is due to an altered nitric oxide signalling mechanism in skeletal
muscle arterioles, but is not the result of increased arginase activity and limited l -arginine substrate. Rather, the age-related deficit in flow-mediated vasodilatation appears to be the result, in part, of
limited BH 4 bioavailability.
Coronary microvascular function and blood flow responses during acute exercise are impaired in the aged heart but can be restored by exercise training. Coronary microvascular resistance is directly ...dependent on vascular smooth muscle function in coronary resistance arterioles; therefore, we hypothesized that age impairs contractile function and alters the phenotype of vascular smooth muscle in coronary arterioles. We further hypothesized that exercise training restores contractile function and reverses age-induced phenotypic alterations of arteriolar smooth muscle. Young and old Fischer 344 rats underwent 10 wk of treadmill exercise training or remained sedentary. At the end of training or cage confinement, contractile responses, vascular smooth muscle proliferation, and expression of contractile proteins were assessed in isolated coronary arterioles. Both receptor- and non-receptor-mediated contractile function were impaired in coronary arterioles from aged rats. Vascular smooth muscle shifted from a differentiated, contractile phenotype to a secretory phenotype with associated proliferation of smooth muscle in the arteriolar wall. Expression of smooth muscle myosin heavy chain 1 (SM1) was decreased in arterioles from aged rats, whereas expression of phospho-histone H3 and of the synthetic protein ribosomal protein S6 (rpS6) were increased. Exercise training improved contractile responses, reduced smooth muscle proliferation and expression of rpS6, and increased expression of SM1 in arterioles from old rats. Thus age-induced contractile dysfunction of coronary arterioles and emergence of a secretory smooth muscle phenotype may contribute to impaired coronary blood flow responses, but arteriolar contractile responsiveness and a younger smooth muscle phenotype can be restored with late-life exercise training. NEW & NOTEWORTHY Aging impairs contractile function of coronary arterioles and induces a shift of the vascular smooth muscle toward a proliferative, noncontractile phenotype. Late-life exercise training reverses contractile dysfunction of coronary arterioles and restores a young phenotype to the vascular smooth muscle.
Astronauts are reported to have experienced some impairment in visual acuity during their mission on the International Space Station (ISS) and after they returned to Earth. There is emerging evidence ...that changes in vision may involve alterations in ocular structure and function. To investigate possible mechanisms, changes in protein expression profiles and oxidative stress-associated apoptosis were examined in mouse ocular tissue after spaceflight. Nine-week-old male C57BL/6 mice (
= 12) were launched from the Kennedy Space Center on a SpaceX rocket to the ISS for a 35-day mission. The animals were housed in the mouse Habitat Cage Unit (HCU) in the Japan Aerospace Exploration Agency (JAXA) "Kibo" facility on the ISS. The flight mice lived either under an ambient microgravity condition (µg) or in a centrifugal habitat unit that produced 1
artificial gravity (µg + 1
). Habitat control (HC) and vivarium control mice lived on Earth in HCUs or normal vivarium cages, respectively. Quantitative assessment of ocular tissue demonstrated that the µg group induced significant apoptosis in the retina vascular endothelial cells compared to all other groups (
< 0.05) that was 64% greater than that in the HC group. Proteomic analysis showed that many key pathways responsible for cell death, cell repair, inflammation, and metabolic stress were significantly altered in µg mice compared to HC animals. Additionally, there were more significant changes in regulated protein expression in the µg group relative to that in the µg + 1
group. These data provide evidence that spaceflight induces retinal apoptosis of vascular endothelial cells and changes in retinal protein expression related to cellular structure, immune response and metabolic function, and that artificial gravity (AG) provides some protection against these changes. These retinal cellular responses may affect blood⁻retinal barrier (BRB) integrity, visual acuity, and impact the potential risk of developing late retinal degeneration.
Ageing reduces endothelium-dependent vasodilatation in humans and animals, and in humans, exercise training reverses the ageing-associated
reduction in endothelium-dependent vasodilatation. The ...purpose of this study was to determine the mechanism(s) by which 10â12
weeks of treadmill exercise enhances endothelium-dependent vasodilatation in muscles of differing fibre composition from young
and old rats. Three- and 22-month-old male Fischer 344 rats were assigned to young sedentary, young exercise-trained, old
sedentary, or old exercise-trained groups. Arterioles were isolated from the soleus and gastrocnemius muscles; luminal diameter
changes were determined in response to the endothelium-dependent vasodilator acetylcholine (ACh, 10 â9 â10 â4 mol l â1 ) alone and in the presence of the nitric oxide synthase (NOS) inhibitor l -NAME (10 â5 mol l â1 ) or the combination of l -NAME and the cyclooxygenase inhibitor indomethacin (10 â5 mol l â1 ). Training ameliorated the ageing-induced reduction in endothelium-dependent vasodilatation in soleus muscle arterioles.
Treatment with l -NAME alone and in combination with indomethacin abolished differences in ACh vasodilatation occurring with ageing and training.
Expression of endothelial NOS (eNOS) mRNA in soleus arterioles was unaltered by ageing, whereas eNOS protein was increased
with age; training elevated both eNOS mRNA and protein. In gastrocnemius muscle arterioles, ageing did not alter maximal vasodilatation,
but ageing and training increased maximal arteriolar diameter. These results demonstrate that ageing-induced reductions and
training-induced enhancement of endothelial vasodilatation both occur through the nitric oxide signalling mechanism in highly
oxidative skeletal muscle, but ageing and training do not appear to act on the same portion of the signalling cascade.
Age is known to induce remodeling and stiffening of large-conduit arteries; however, little is known of the effects of age on remodeling and mechanical properties of coronary resistance arteries. We ...employed a rat model of aging to investigate whether 1) age increases wall thickness and stiffness of coronary resistance arteries, and 2) exercise training reverses putative age-induced increases in wall thickness and stiffness of coronary resistance arteries. Young (4 mo) and old (21 mo) Fischer 344 rats remained sedentary or underwent 10 wk of treadmill exercise training. Coronary resistance arteries were isolated for determination of wall-to-lumen ratio, effective elastic modulus, and active and passive responses to changes in intraluminal pressure. Elastin and collagen content of the vascular wall were assessed histologically. Wall-to-lumen ratio increased with age, but this increase was reversed by exercise training. In contrast, age reduced stiffness, and exercise training increased stiffness in coronary resistance arteries from old rats. Myogenic responsiveness was reduced with age and restored by exercise training. Collagen-to-elastin ratio (C/E) of the wall did not change with age and was reduced with exercise training in arteries from old rats. Thus age induces hypertrophic remodeling of the vessel wall and reduces the stiffness and myogenic function of coronary resistance arteries. Exercise training reduces wall-to-lumen ratio, increases wall stiffness, and restores myogenic function in aged coronary resistance arteries. The restorative effect of exercise training on myogenic function of coronary resistance arteries may be due to both changes in vascular smooth muscle phenotype and expression of extracellular matrix proteins.
Blood flow capacity in skeletal muscle declines with age. Reduced blood flow capacity may be related to decline in the maximal vasodilatory capacity of the resistance vasculature. This study tested ...the hypothesis that aging results in impaired vasodilatory capacity of first-order (1A) arterioles isolated from rat-hindlimb locomotory muscle: 1A arterioles (90-220 microm) from gastrocnemius and soleus muscles of young (4 mo) and aged (24 mo) Fischer-144 rats were isolated, cannulated, and pressurized via hydrostatic reservoirs. Vasodilatory responses to increasing concentrations of ACh (10(-9) to 10(-4) M), adenosine (ADO, 10(-10) to 10(-4) M), and sodium nitroprusside (SNP, 10(-10) to 10(-4) M) were evaluated at a constant intraluminal pressure of 60 cmH(2)O in the absence of flow. Flow-induced vasodilation was also evaluated in the absence of pressure changes. Responses to ADO and SNP were not altered by age. Endothelium-dependent vasodilation induced by flow was significantly reduced in arterioles from both gastrocnemius and soleus muscles. In contrast, endothelium-dependent vasodilation to ACh was reduced only in soleus muscle arterioles. These results indicate that aging impairs vasodilatory responses mediated through the endothelium of resistance arterioles from locomotory muscle, whereas smooth muscle vasodilatory responses remain intact with aging. Additionally, ACh-induced vasodilation was altered by age only in soleus muscle arterioles, suggesting that the mechanism of age-related endothelial impairment differs in arterioles from soleus and gastrocnemius muscles.
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