Caloric restriction enhances vascular tone of cerebral and mesenteric resistance arteries in aged rats
Introduction
Ageing is a major independent risk factor for cardiovascular diseases (CVDs) (Najjar et al., 2005), (Lakatta and Levy, 2003), and is significantly associated with increased incidence of hypertension, heart disease and stroke (Lakatta and Levy, 2003), (Kovacic et al., 2011). With advancing age both mechanical factors, such as pressure-induced wall stress and blood pressure, and other pressure-independent risk factors, such as atherosclerosis, can induce progressive structural and functional changes within the microcirculation which contribute to the development of CVDs (Najjar et al., 2005), (Lakatta and Levy, 2003), (Ungvari et al., 2018a).
As ageing advances, biomechanical changes of resistance arteries have been associated with increased lumen diameter and wall thickness within the vasculature (Briones et al., 2007), (Moreau et al., 1998), (Mandalà et al., 2012), (Diaz-Otero et al., 2016). Outward hypertrophic remodelling in addition to arterial stiffness (Jani and Rajkumar, 2006), (Lee and Oh, 2010) and reduced elasticity of the arterial wall (Mandalà et al., 2012) can compromise vascular compliance (Blacher and Safar, 2005), (Jani and Rajkumar, 2006) and underlies the ageing-related vascular dysfunction (Donato et al., 2018).
Amongst potential mechanisms the interplay between increased oxidative stress and the upregulation of inflammatory processes plays a key role in mediating vascular changes associated with age (Csiszar et al., 2008). Evidence in animals (Csiszar et al., 2002), (van der Loo et al., 2000), (Sun et al., 2004), (Hamilton et al., 2001), (Csiszar et al., 2007), and humans (Donato et al., 2007), (Jablonski et al., 2007), (Rodríguez-Mañas et al., 2009), suggests that exacerbated mechanisms of oxidative stress and inflammation, leading to pro-inflammatory effects, strongly impairs vascular function with advancing age. Levels of pro-inflammatory factors (Donato et al., 2008), (Rippe et al., 2012) and markers of vascular oxidative stress (Gano et al., 2011), have been found increased in aged humans.
Dietary approaches aiming to improve plasma and tissue redox and inflammatory profiles may offer a beneficial intervention to attenuate the rapid progression of age-related CVDs and increase longevity (Brandhorst and Longo, 2019). CR, a chronic and coordinate reduction in food intake without causing malnutrition, is a promising option against age-related oxidative stress and inflammation (Mercken et al., 2013), (La Russa et al., 2020), (Yang et al., 2004). Powerful protective effects of CR have been reported to improve lifespan (Fontana et al., 2010) and shown to reduce risks associated with myocardial stiffness and atherosclerosis in humans (Meyer et al., 2006), (Fontana et al., 2004). In aged mice, lifelong CR has been shown to reduce superoxide production and ameliorate endothelial dysfunction in cerebral resistance arteries (Walker et al., 2014).
In previous animal studies, we (Mandalà et al., 2012) and others (Diaz-Otero et al., 2016), (Springo et al., 2015), have demonstrated that changes of biomechanical properties and tone of cerebral resistance arteries are associated with ageing. Hence, we tested the hypothesis that CR would improve biomechanical properties and reactivity of cerebral resistance arteries to protect the cerebrovasculature in aged rats. Further, to evaluate if CR action is vascular bed-dependent, the effects of CR were investigated also in the systemic circulation of aged rats, by including mesenteric resistance arteries in the study.
Section snippets
Animals
The present study was conducted in accordance with the European Guidelines on the protection of animals used for scientific purposes (Directive 2010/63/EU) and was approved by the local ethical committee of the University of Calabria and the Italian Institutional Animal Care (license n.295/2016-PR). Male Sprague-Dawley rats (n = 25) were housed under controlled conditions on a 12-h light/dark cycle at 20–22 °C. Standard chow (ssniff diet V1535, German; metabolisable energy 3.057 Kcal/Kg) and
Results
At 18 months, there was no difference in body weight between controls and CR rats (body weight: control, 686.3 ± 27.4 g vs FR, 639.1 ± 27.9 g). 24 old months rats had a significantly reduced body weight after food restriction compared with age-matched rats with free access to food (p < 0.0001; body weight: control, 655.7 ± 23.97 g vs FR, 424.4 ± 14.1 g; Fig. 1A).
Discussion
In this study we evaluated the effect of CR on functional and biomechanical properties of small resistance vessels, the cerebral and mesenteric arteries, in aged (24 months old) rats. As main findings, our results show that six months of CR enhances vascular tone in cerebral and mesenteric arteries and exerts minor effects on vascular remodelling of both vessels.
Small-sized arteries are the major regulators of vascular resistance and critically control blood flow and perfusion pressure to
Conclusions
In conclusion, our present results indicate that CR can improve age-associated changes of tone of cerebral and mesenteric resistance arteries. Vascular bed-independent effects of limited food intake are of relevance for reducing the overall risk of developing CVDs, and delineating the mechanisms by which this approach acts at both local and systemic level in aged individuals will be paramount to improve vascular health span.
Funding
This study was supported by the University of Calabria, Italy.
References (62)
- et al.
Protein quantity and source, fasting-mimicking diets, and longevity
Adv. Nutr.
(2019) - et al.
Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women
J. Am. Coll. Cardiol.
(1994) - et al.
Increased expression of endothelin-1 and inducible nitric oxide synthase isoform ii in aging arteries in vivo: implications for atherosclerosis
Biochem. Biophys. Res. Commun.
(2001) - et al.
Tetrahydrobiopterin improves aging-related impairment of endothelium-dependent vasodilation through increase in nitric oxide production
Atherosclerosis
(2006) - et al.
Long-term caloric restriction ameliorates the decline in diastolic function in humans
J. Am. Coll. Cardiol.
(2006) - et al.
Phosphodiesterase-3 inhibitor cilostazol reverses endothelial dysfunction with ageing in rat mesenteric resistance arteries
Eur. J. Pharmacol.
(2018) - et al.
Mechanical stretching stimulates smooth muscle cell growth, nuclear protein import, and nuclear pore expression through mitogen-activated protein kinase activation
J. Biol. Chem.
(2007) - et al.
Microrna changes in human arterial endothelial cells with senescence: relation to apoptosis, enos and inflammation
Exp. Gerontol.
(2012) - et al.
Ampk induces vascular smooth muscle cell senescence Via Lkb1 dependent pathway
Biochem. Biophys. Res. Commun.
(2011) - et al.
Large-artery stiffness, hypertension and cardiovascular risk in older patients
Nat. Clin. Pract. Cardiovasc. Med.
(2005)
Mechanisms underlying hypertrophic remodeling and increased stiffness of mesenteric resistance arteries from aged rats
J. Gerontol. A Biol. Sci. Med. Sci.
Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats
Circ. Res.
Loss of expression of the beta subunit of soluble guanylyl cyclase prevents nitric oxide-mediated inhibition of Dna synthesis in smooth muscle cells of old rats
Circ. Res.
Influence of constriction, wall tension, smooth muscle activation and cellular deformation on rat resistance artery vasodilator reactivity
Cell. Physiol. Biochem.
Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function
Circ. Res.
Vascular aging in the longest-living rodent, the naked mole rat
Am. J. Physiol. Heart Circ. Physiol.
Inflammation and endothelial dysfunction during aging: role of Nf-Kappab
J. Appl. Physiol.
Changes in cerebral arteries and parenchymal arterioles with aging: role of rho kinase 2 and impact of genetic background
Hypertension
Aging is associated with changes to the biomechanical properties of the posterior cerebral artery and parenchymal arterioles
Am. J. Physiol. Heart Circ. Physiol.
Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappab
Circ. Res.
Aging is associated with greater nuclear Nf Kappa B, reduced I kappa B alpha, and increased expression of proinflammatory cytokines in vascular endothelial cells of healthy humans
Aging Cell
Mechanisms of dysfunction in the aging vasculature and role in age-related disease
Circ. Res.
Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans
Proc. Natl. Acad. Sci. U. S. A.
Extending healthy life span--from yeast to humans
Science
Increased proinflammatory and oxidant gene expression in circulating mononuclear cells in older adults: amelioration by habitual exercise
Physiol. Genomics
Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans
Hypertension
Age impaired endothelium-dependent vasodilation is improved by resveratrol in rat mesenteric arteries
J. Exerc. Nutrition Biochem.
Risk factors for vascular dementia and alzheimer disease
Stroke
Superoxide excess in hypertension and aging: a common cause of endothelial dysfunction
Hypertension
High-dose ascorbic acid infusion abolishes chronic vasoconstriction and restores resting leg blood flow in healthy older men
J. Appl. Physiol.
Ageing and vascular ageing
Postgrad. Med. J.
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