Anthracycline chemotherapy‐mediated vascular dysfunction as a model of accelerated vascular aging

Aging is a primary risk factor for cardiovascular disease (CVD), which is the leading cause of death in developed countries. Globally, the population of adults over the age of 60 is expected to double by the year 2050. CVD prevalence and mortality rates differ between men and women as they age in part due to sex-specific mechanisms impacting the biological processes of aging. Measures of vascular function offer key insights into cardiovascular health. Changes in vascular function precede changes in CVD prevalence rates in men and women and with aging. A key mechanism underlying these changes in vascular function is the endothelin (ET) system. Studies have demonstrated sex and sex hormone effects on endothelin-1 (ET-1), and its receptors ETA and ETB. However, with aging there is a dysregulation of this system resulting in an imbalance between vasodilation and vasoconstriction. Thus, ET-1 may play a role in the sex differences observed with vascular aging. While most research has been conducted in pre-clinical animal models, we describe more recent translational data in humans showing that the ET system is an important regulator of vascular dysfunction with aging and acts through sex-specific ET receptor mechanisms. In this review, we present translational evidence (cell, tissue, animal, and human) that the ET system is a key mechanism regulating sex-specific changes in vascular function with aging, along with therapeutic interventions to reduce ET-mediated vascular dysfunction associated with aging. More knowledge on the factors responsible for the sex differences with vascular aging allow for optimized therapeutic strategies to attenuate CVD risk in the expanding aging population.

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Abstract T MP114: PPARγ in Endothelial Cells Plays an Essential Role in Protecting Against Vascular Aging: Role of Oxidative Stress and Rho Kinase

Stroke ◽

10.1161/str.45.suppl_1.tmp114 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Dale Kinzenbaw ◽

T. Micheal De Silva ◽

Curt Sigmund ◽

Frank M Faraci

Keyword(s):

Oxidative Stress ◽

Endothelial Function ◽

Vascular Disease ◽

Vascular Dysfunction ◽

Rho Kinase ◽

Dominant Negative ◽

Vascular Aging ◽

Dominant Negative Mutation ◽

Age Related

Although aging is the greatest risk factor for vascular disease and stroke, relatively little is known regarding mechanisms that regulate vascular aging. Endothelial dysfunction - a key element of carotid artery and cerebrovascular disease - progresses with age, greatly increasing the risk for ischemic stroke and cognitive impairment. The nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) is a ligand-activated transcription factor that may exert diverse effects depending on the cell type. Because little is known regarding the role of PPARγ in vascular aging, we used transgenic mice expressing a dominant negative mutation in human PPARγ (V290M) under control of the endothelial-specific vascular cadherin promoter (designated E-V290M) to examine the hypothesis that cell-specific interference with PPARγ would promote age-induced vascular dysfunction. Responses of carotid arteries from adult (11-12 mo) and old (24±1 mo) E-V290M mice and non-transgenic littermates were examined in vitro. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of arteries from adult control and E-V290M mice as well as old control mice. In contrast, responses to acetylcholine in arteries from old E-V290M mice were reduced by more than 50% in old E-V290M mice (P<0.01). Endothelial function in old E-V290M mice was not altered by indomethacin but was restored to normal by tempol (a superoxide scavenger) or VAS-2870 (an inhibitor of NADPH oxidase). Reactive oxygen species can activate Rho kinase (a potential mediator of vascular disease) and inhibition of Rho kinase with Y-27632 restored endothelial function to normal in old E-V290M mice. Relaxation of arteries to nitroprusside, which acts directly on vascular muscle, was similar in all groups. These findings provide the first evidence that age-related vascular dysfunction is accelerated following cell-specific interference with endothelial PPARγ through mechanisms involving oxidative stress and Rho kinase. This novel role for endothelial PPARγ has implications for understanding vascular pathophysiology as well as therapeutic approaches for age-induced large and small vessel disease.

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Healthy lifestyle-based approaches for successful vascular aging

Journal of Applied Physiology ◽

10.1152/japplphysiol.00521.2018 ◽

2018 ◽

Vol 125 (6) ◽

pp. 1888-1900 ◽

Cited By ~ 16

Author(s):

Matthew J. Rossman ◽

Thomas J. LaRocca ◽

Christopher R. Martens ◽

Douglas R. Seals

Keyword(s):

Dietary Patterns ◽

Healthy Lifestyle ◽

Vascular Dysfunction ◽

Lifestyle Behaviors ◽

Vascular Aging ◽

First Line ◽

Gerontological Society ◽

Age Related ◽

Alternative Approaches ◽

Recommended Guidelines

This review summarizes a presentation given at the 2016 Gerontological Society of America Annual Meeting as part of the Vascular Aging Workshop. The development of age-related vascular dysfunction increases the risk of cardiovascular disease as well as other chronic age-associated disorders, including chronic kidney disease and Alzheimer’s disease. Healthy lifestyle behaviors, most notably regular aerobic exercise and certain dietary patterns, are considered “first-line” strategies for the prevention and/or treatment of vascular dysfunction with aging. Despite the well-established benefits of these strategies, however, many older adults do not meet the recommended guidelines for exercise or consume a healthy diet. Therefore, it is important to establish alternative and/or complementary evidence-based approaches to prevent or reverse age-related vascular dysfunction. Time-efficient forms of exercise training, hormetic exposure to mild environmental stress, fasting “mimicking” dietary paradigms, and nutraceutical/pharmaceutical approaches to favorably modulate cellular and molecular pathways activated by exercise and healthy dietary patterns may hold promise as such alternative approaches. Determining the efficacy of these novel strategies is important to provide alternatives for adults with low adherence to conventional healthy lifestyle practices for healthy vascular aging.

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Ιmmunity, Vascular Aging, and Stroke

Current Medicinal Chemistry ◽

10.2174/0929867329666220103101700 ◽

2022 ◽

Vol 29 ◽

Author(s):

Anna-Maria Louka ◽

Dimitrios Sagris ◽

George Ntaios

Keyword(s):

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Brain Barrier ◽

Low Grade ◽

Vascular Aging ◽

Barrier Dysfunction ◽

Blood Brain

Abstract: Stroke is one of the most devastating manifestations of cardiovascular disease. Growing age, arterial hypertension, and atherosclerosis are identified as independent risk factors for stroke, primarily due to structural and functional alterations in the cerebrovascular tree. Recent data from in vitro and clinical studies have suggested that the immune system influences atherosclerosis, promoting vascular stiffness and vascular aging and contributing to ischemic stroke, intracranial haemorrhage and microbleeds, white matter disease, and cognitive decline. Furthermore, aging is related to a chronic low-grade inflammatory state, in which macrophage, neutrophils, natural killer (NK cells), and B and T lymphocytes act as major effectors of the immune-mediated cell responses. Moreover, oxidative stress and vascular inflammation are correlated with endothelial dysfunction, vascular aging, blood-brain barrier disruption, lacunar lesions, and neurodegenerative disorders. This review discusses the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including the complex interplay between them and innate immunity, as well as vascular dysfunction, arterial stiffness, atherosclerosis, atherothrombosis, systemic inflammation, and blood-brain barrier dysfunction.

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Vascular and Endothelial Biology of Aging

Blood ◽

10.1182/blood.v126.23.sci-5.sci-5 ◽

2015 ◽

Vol 126 (23) ◽

pp. SCI-5-SCI-5

Author(s):

Frank M. Faraci

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Transgenic Mice ◽

Nadph Oxidase ◽

Endothelial Function ◽

Vascular Dysfunction ◽

Rho Kinase ◽

Vascular Aging ◽

Age Related ◽

The Brain

Abstract Although aging is one of the greatest risk factors for vascular disease, very little is known regarding mechanisms that control the progression of vascular aging at the level of the endothelial cell. Endothelial dysfunction - a critical element of carotid artery and cerebrovascular disease - progresses with age, contributing to hypoperfusion, increased risk for ischemic stroke, and cognitive decline. Studies from several laboratories support the concept that age-induced endothelial dysfunction may occur earlier and be larger in magnitude in the cerebral circulation than in blood vessels outside of the brain. Thus, the circulationof the brain may be particularly sensitive to age-induced endothelial dysfunction. In relation to underlying mechanisms, angiotensin II type 1 receptors, NADPH oxidase, and oxidative stress appear to play a key role in age-related vascular dysfunction. The nuclear receptor peroxisome proliferator-activated receptor-g (PPARg) exerts protective effects in the vasculature when pharmacologically activated. We recently examined the hypothesis that endothelial PPARg protects against vascular aging. We studied carotid arteries from adult and old transgenic mice with endothelial specific expression of a human dominant negative mutation in PPARg driven by the vascular cadherin promoter (designated E-V290M), along with non-transgenic littermates. Endothelial function was similar in arteries from adult non-transgenic and E-V290M mice as well as old non-transgenic mice. In contrast, there was a marked reduction in endothelial function in old E-V290M mice. This augmented endothelial dysfunction was not altered by inhibition of cyclooxygenase, but was restored to normal by a superoxide scavenger, an inhibitor of NADPH oxidase, or inhibition of Rho kinase. Oxidant and inflammatory related mechanisms often interact. Vascular expression of interleukin-6, another mediator of vascular disease, was increased 1.6-fold in old non-transgenic mice, but almost 9-fold in old E-V290M mice. Expression of CDKN2A, a molecular marker of senescence, was ~two-fold greater in old E-V290M mice compared to controls. These findings provide the first evidence that senescence and age-related vascular dysfunction is accelerated following cell-specific interference with endothelial PPARg through mechanisms that involve oxidative stress, inflammation, and Rho kinase. This critical role for endothelial PPARg has implications for vascular pathophysiology as well as therapeutic approaches for age-induced large and small vessel disease. Disclosures No relevant conflicts of interest to declare.

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Role of endothelial NAD+ deficiency in age-related vascular dysfunction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00039.2019 ◽

2019 ◽

Vol 316 (6) ◽

pp. H1253-H1266 ◽

Cited By ~ 20

Author(s):

Anna Csiszar ◽

Stefano Tarantini ◽

Andriy Yabluchanskiy ◽

Priya Balasubramanian ◽

Tamas Kiss ◽

...

Keyword(s):

Older Adults ◽

Molecular Mechanisms ◽

Cardiovascular Health ◽

Therapeutic Potential ◽

Vascular Dysfunction ◽

Model Organisms ◽

Vascular Aging ◽

Health Span ◽

Comprehensive Overview ◽

Age Related

Age-related alterations in endothelium and the resulting vascular dysfunction critically contribute to a range of pathological conditions associated with old age. To develop therapies rationally that improve vascular health and thereby increase health span and life span in older adults, it will be essential to understand the cellular and molecular mechanisms contributing to vascular aging. Preclinical studies in model organisms demonstrate that NAD+ availability decreases with age in multiple tissues and that supplemental NAD+ precursors can ameliorate many age-related cellular impairments. Here, we provide a comprehensive overview of NAD+-dependent pathways [including the NAD+-using silent information regulator-2-like enzymes and poly(ADP-ribose) polymerase enzymes] and the potential consequences of endothelial NAD+ deficiency in vascular aging. The multifaceted vasoprotective effects of treatments that reverse the age-related decline in cellular NAD+ levels, as well as their potential limitations, are discussed. The preventive and therapeutic potential of NAD+ intermediates as effective, clinically relevant interventions in older adults at risk for ischemic heart disease, vascular cognitive impairment, and other common geriatric conditions and diseases that involve vascular pathologies (e.g., sarcopenia, frailty) are critically discussed. We propose that NAD+ precursors [e.g., nicotinamide (Nam) riboside, Nam mononucleotide, niacin] should be considered as critical components of combination therapies to slow the vascular aging process and increase cardiovascular health span.

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New Insight into the Mechanisms of Ginkgo Biloba Extract in Vascular Aging Prevention

Current Vascular Pharmacology ◽

10.2174/1570161117666190621150725 ◽

2020 ◽

Vol 18 (4) ◽

pp. 334-345 ◽

Cited By ~ 1

Author(s):

Xiaoxue Li ◽

Liuyi Lu ◽

Jie Chen ◽

Chao Zhang ◽

Hong Chen ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Ginkgo Biloba ◽

Vascular Dysfunction ◽

Ginkgo Biloba Extract ◽

Vascular Aging ◽

Glucose And Lipid Metabolism ◽

Promising Therapeutic Approach ◽

Underlying Mechanisms ◽

Main Effects ◽

Insight Into

Background: Aging-associated vascular dysfunction promotes cardiovascular diseases. Recently, Ginkgo biloba extract (GBE) has attracted considerable attention in the prevention of aged vasculature. Methods: This review discusses the pathophysiological alterations in aged vasculature and the underlying mechanisms of GBE in vascular aging suppression. Results: Both arterial stiffening and endothelial dysfunction are critical aging-related vascular phenotypes that result in the progression of cardiovascular diseases in the general population. Consistent oxidative stress and inflammatory reaction lead to vascular dysfunction. GBE ameliorates aging-related vascular dysfunction, due to its antioxidant and anti-inflammatory properties. The main effects of GBE in aged vasculature might be associated with the longevity signaling pathways. GBE also attenuates the progression of vascular aging in diabetes mellitus via regulation of glucose and lipid metabolism. Conclusion: GBE plays an important role in the prevention of vascular aging process. It is a promising therapeutic approach to ameliorate aging-related vascular dysfunction and cardiovascular diseases.

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Abstract 108: Cell-Specific Interference with Endothelial PPARγ Produces Oxidative Stress and Accelerates Vascular Aging

Stroke ◽

10.1161/str.43.suppl_1.a108 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Mary L Modrick ◽

Dale A Kinzenbaw ◽

Pimonrat Ketsawatsomkron ◽

Curt D Sigmund ◽

Frank M Faraci

Keyword(s):

Oxidative Stress ◽

Carotid Artery ◽

Vascular Disease ◽

Carotid Arteries ◽

Vascular Dysfunction ◽

Dominant Negative ◽

Nitric Oxide Donor ◽

Vascular Aging ◽

Dominant Negative Mutation ◽

Age Related

Despite the fact that aging is the greatest risk factor for vascular disease and stroke, relatively little is known regarding mechanisms that promote or protect against vascular aging in experimental models or people. Endothelial dysfunction is a key contributor to both the initiation and progression of vascular disease. Atherosclerosis in carotid arteries (carotid artery disease) greatly increases the risk for ischemic stroke and may contribute to dementia (including Alzheimer’s disease). Peroxisome proliferator activated receptor-γ (PPARγ) is a ligand-activated transcription factor that exerts diverse effects depending on the cell type. Recent work suggests that PPARγ can have beneficial effects in the vasculature including protection against oxidative stress. Relatively little is known regarding the potential role of PPARγ in aging. We used transgenic mice expressing a dominant negative mutation in human PPARγ (V290M) under control of the endothelial-specific vascular cadherin promoter (designated E-V290M) to examine the hypothesis that interference with endothelial PPARγ will promote age-induced vascular dysfunction. Responses of carotid arteries from adult (6±1 mo) and old (23±1 mo) E-V290M mice and non-transgenic littermates (controls) were examined in vitro. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of arteries from adult control and E-V290M mice as well as old control mice. In contrast, responses to acetylcholine in arteries from old E-V290M mice were markedly impaired. For example, relaxation of the carotid artery to 10 µmol/L acetylcholine was 84±3 and 40±6% in old control versus old E-V290M mice, respectively (P<0.01). The impaired response to acetylcholine in old E-V290M mice could be restored to normal (81±4% relaxation) by tempol, a scavenger of superoxide. Relaxation of the carotid artery to nitroprusside (a nitric oxide donor that acts directly on vascular muscle) was similar in all groups. These findings provide the first evidence that age-related vascular dysfunction is accelerated following cell-specific interference with endothelial PPARγ function. The mechanism that accounts for this change appears to involve reactive oxygen species. Our findings suggest a major protective role for endothelial PPARγ in age-induced oxidative stress and vascular dysfunction.

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Inorganic nitrite supplementation for healthy arterial aging

Journal of Applied Physiology ◽

10.1152/japplphysiol.01100.2013 ◽

2014 ◽

Vol 116 (5) ◽

pp. 463-477 ◽

Cited By ~ 36

Author(s):

Amy L. Sindler ◽

Allison E. DeVan ◽

Bradley S. Fleenor ◽

Douglas R. Seals

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Therapeutic Potential ◽

Vascular Dysfunction ◽

Aortic Pulse Wave Velocity ◽

Vascular Aging ◽

Age Related ◽

Arterial Aging ◽

Artery Stiffness ◽

Elastic Artery

Aging is the major risk factor for cardiovascular diseases (CVD). This is attributable primarily to adverse changes in arteries, notably, increases in large elastic artery stiffness and endothelial dysfunction mediated by inadequate concentrations of the vascular-protective molecule, nitric oxide (NO), and higher levels of oxidative stress and inflammation. Inorganic nitrite is a promising precursor molecule for augmenting circulating and tissue NO bioavailability because it requires only a one-step reduction to NO. Nitrite also acts as an independent signaling molecule, exerting many of the effects previously attributed to NO. Results of recent studies indicate that nitrite may be effective in the treatment of vascular aging. In old mice, short-term oral sodium nitrite supplementation reduces aortic pulse wave velocity, the gold-standard measure of large elastic artery stiffness, and ameliorates endothelial dysfunction, as indicated by normalization of NO-mediated endothelium-dependent dilation. These improvements in age-related vascular dysfunction with nitrite are mediated by reductions in oxidative stress and inflammation, and may be linked to increases in mitochondrial biogenesis and health. Increasing nitrite levels via dietary intake of nitrate appears to have similarly beneficial effects in many of the same physiological and clinical settings. Several clinical trials are being performed to determine the broad therapeutic potential of increasing nitrite bioavailability on human health and disease, including studies related to vascular aging. In summary, inorganic nitrite, as well as dietary nitrate supplementation, represents a promising therapy for treatment of arterial aging and prevention of age-associated CVD in humans.

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Targeting mitochondrial fitness as a strategy for healthy vascular aging

Clinical Science ◽

10.1042/cs20190559 ◽

2020 ◽

Vol 134 (12) ◽

pp. 1491-1519 ◽

Cited By ~ 1

Author(s):

Matthew J. Rossman ◽

Rachel A. Gioscia-Ryan ◽

Zachary S. Clayton ◽

Michael P. Murphy ◽

Douglas R. Seals

Keyword(s):

Oxidative Stress ◽

Carotid Arteries ◽

Vascular Dysfunction ◽

Current Evidence ◽

Vascular Aging ◽

Cvd Risk ◽

Age Related ◽

Vascular Oxidative Stress ◽

Primary Risk Factor ◽

Related Increase

Abstract Cardiovascular diseases (CVD) are the leading cause of death worldwide and aging is the primary risk factor for CVD. The development of vascular dysfunction, including endothelial dysfunction and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries), contribute importantly to the age-related increase in CVD risk. Vascular aging is driven in large part by oxidative stress, which reduces bioavailability of nitric oxide and promotes alterations in the extracellular matrix. A key upstream driver of vascular oxidative stress is age-associated mitochondrial dysfunction. This review will focus on vascular mitochondria, mitochondrial dysregulation and mitochondrial reactive oxygen species (ROS) production and discuss current evidence for prevention and treatment of vascular aging via lifestyle and pharmacological strategies that improve mitochondrial health. We will also identify promising areas and important considerations (‘research gaps’) for future investigation.

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