Age-related Vascular Pathologies Research Articles

Identification of cellular heterogeneity and key signaling pathways associated with vascular remodeling and calcification in young and old primate aortas based on single-cell analysis.

Aging of the vascular system is the main cause of many cardiovascular diseases. The structure and function of the blood vessel wall change with aging. To prevent age-related cardiovascular diseases, it is essential to understand the cellular heterogeneity of vascular wall and changes of cellular communication among cell subpopulations during aging. Here, using published single-cell RNA sequencing datasets of young and old monkey aortas, we analyzed the heterogeneity of vascular endothelial cells and smooth muscle cells in detail and identified a distinct endothelial cell subpopulation that involved in vascular remodeling and calcification. Moreover, cellular communication that changed with aging was analyzed and we identified a number of signaling pathways that associated with vascular aging. We found that EGF signaling pathway play an essential role in vascular remodeling and calcification of aged aortas. This work provided a better understanding of vascular aging and laid the foundation for prevention of age-related vascular pathologies.

Endogenous Vasoactive Peptides and Vascular Aging-Related Diseases.

Vascular aging is a specific type of organic aging that plays a central role in the morbidity and mortality of cardiovascular and cerebrovascular diseases among the elderly. It is essential to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes. Endogenous vasoactive peptides are compounds formed by a group of amino acids connected by peptide chains that exert regulatory roles in intercellular interactions involved in a variety of biological and pathological processes. Emerging evidence suggests that a variety of vasoactive peptides play important roles in the occurrence and development of vascular aging and related diseases such as atherosclerosis, hypertension, vascular calcification, abdominal aortic aneurysms, and stroke. This review will summarize the cumulative roles and mechanisms of several important endogenous vasoactive peptides in vascular aging and vascular aging-related diseases. In addition, we also aim to explore the promising diagnostic function as biomarkers and the potential therapeutic application of endogenous vasoactive peptides in vascular aging-related diseases.

Age-related alterations in the cerebrovasculature affect neurovascular coupling and BOLD fMRI responses: Insights from animal models of aging.

The present and future research efforts in cognitive neuroscience and psychophysiology rely on the measurement, understanding, and interpretation of blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to effectively investigate brain function. Aging and age-associated pathophysiological processes change the structural and functional integrity of the cerebrovasculature which can significantly alter how the BOLD signal is recorded and interpreted. In order to gain an improved understanding of the benefits, drawbacks, and methodological implications for BOLD fMRI in the context of cognitive neuroscience, it is crucial to understand the cellular and molecular mechanism of age-related vascular pathologies. This review discusses the multifaceted effects of aging and the contributions of age-related pathologies on structural and functional integrity of the cerebral microcirculation as they has been investigated in animal models of aging, including age-related alterations in neurovascular coupling responses, cellular and molecular mechanisms involved in microvascular damage, vascular rarefaction, blood-brain barrier disruption, senescence, humoral deficiencies as they relate to, and potentially introduce confounding factors in the interpretation of BOLD fMRI.

Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects.

Understanding molecular mechanisms involved in vascular aging is essential to develop novel interventional strategies for treatment and prevention of age-related vascular pathologies. Recent studies provide critical evidence that vascular aging is characterized by NAD+ depletion. Importantly, in aged mice, restoration of cellular NAD+ levels by treatment with the NAD+ booster nicotinamide mononucleotide (NMN) exerts significant vasoprotective effects, improving endothelium-dependent vasodilation, attenuating oxidative stress, and rescuing age-related changes in gene expression. Strong experimental evidence shows that dysregulation of microRNAs (miRNAs) has a role in vascular aging. The present study was designed to test the hypothesis that age-related NAD+ depletion is causally linked to dysregulation of vascular miRNA expression. A corollary hypothesis is that functional vascular rejuvenation in NMN-treated aged mice is also associated with restoration of a youthful vascular miRNA expression profile. To test these hypotheses, aged (24-month-old) mice were treated with NMN for 2weeks and miRNA signatures in the aortas were compared to those in aortas obtained from untreated young and aged control mice. We found that protective effects of NMN treatment on vascular function are associated with anti-aging changes in the miRNA expression profile in the aged mouse aorta. The predicted regulatory effects of NMN-induced differentially expressed miRNAs in aged vessels include anti-atherogenic effects and epigenetic rejuvenation. Future studies will uncover the mechanistic role of miRNA gene expression regulatory networks in the anti-aging effects of NAD+ booster treatments and determine the links between miRNAs regulated by NMN and sirtuin activators and miRNAs known to act in the conserved pathways of aging and major aging-related vascular diseases.

Mechanisms of Vascular Aging.

Aging of the vasculature plays a central role in morbidity and mortality of older people. To develop novel treatments for amelioration of unsuccessful vascular aging and prevention of age-related vascular pathologies, it is essential to understand the cellular and functional changes that occur in the vasculature during aging. In this review, the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including oxidative stress, mitochondrial dysfunction, impaired resistance to molecular stressors, chronic low-grade inflammation, genomic instability, cellular senescence, epigenetic alterations, loss of protein homeostasis, deregulated nutrient sensing, and stem cell dysfunction in the vascular system are considered in terms of their contribution to the pathogenesis of both microvascular and macrovascular diseases associated with old age. The importance of progeronic and antigeronic circulating factors in relation to development of vascular aging phenotypes are discussed. Finally, future directions and opportunities to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes are presented.

Connective tissue growth factor (CTGF) in age-related vascular pathologies.

Connective tissue growth factor (CTGF, also known as CCN2) is a matricellular protein expressed in the vascular wall, which regulates diverse cellular functions including cell adhesion, matrix production, structural remodeling, angiogenesis, and cell proliferation and differentiation. CTGF is principally regulated at the level of transcription and is induced by mechanical stresses and a number of cytokines and growth factors, including TGFβ. In this mini-review, the role of age-related dysregulation of CTGF signaling and its role in a range of macro- and microvascular pathologies, including pathogenesis of aorta aneurysms, atherogenesis, and diabetic retinopathy, are discussed. A potential role of CTGF and TGFβ in regulation and non-cell autonomous propagation of cellular senescence is also discussed.

Age‐related impairment of endothelial progenitor cell migration correlates with structural alterations of heparan sulfate proteoglycans

Aging poses one of the largest risk factors for the development of cardiovascular disease. The increased propensity toward vascular pathology with advancing age maybe explained, in part, by a reduction in the ability of circulating endothelial progenitor cells to contribute to vascular repair and regeneration. Although there is evidence to suggest that colony forming unit-Hill cells and circulating angiogenic cells are subject to age-associated changes that impair their function, the impact of aging on human outgrowth endothelial cell (OEC) function has been less studied. We demonstrate that OECs isolated from cord blood or peripheral blood samples from young and old individuals exhibit different characteristics in terms of their migratory capacity. In addition, age-related structural changes were discovered in OEC heparan sulfate (HS), a glycocalyx component that is essential in many signalling pathways. An age-associated decline in the migratory response of OECs toward a gradient of VEGF significantly correlated with a reduction in the relative percentage of the trisulfated disaccharide, 2-O-sulfated-uronic acid, N, 6-O-sulfated-glucosamine (UA[2S]-GlcNS[6S]), within OEC cell surface HS polysaccharide chains. Furthermore, disruption of cell surface HS reduced the migratory response of peripheral blood-derived OECs isolated from young subjects to levels similar to that observed for OECs from older individuals. Together these findings suggest that aging is associated with alterations in the fine structure of HS on the cell surface of OECs. Such changes may modulate the migration, homing, and engraftment capacity of these repair cells, thereby contributing to the progression of endothelial dysfunction and age-related vascular pathologies.

Age-Related Vascular Pathology in Transgenic Mice Expressing Presenilin 1-Associated Familial Alzheimer's Disease Mutations

Mutations in the presenilin 1 (PS1) gene are the most commonly recognized cause of familial Alzheimer's disease (FAD). Besides senile plaques, neurofibrillary tangles, and neuronal loss, Alzheimer's disease (AD) is also accompanied by vascular pathology. Here we describe an age-related vascular pathology in two lines of PS1 FAD-mutant transgenic mice that mimics many features of the vascular pathology seen in AD. The pathology was especially prominent in the microvasculature whose vessels became thinned and irregular with the appearance of many abnormally looped vessels as well as string vessels. Stereologic assessments revealed a reduction of the microvasculature in the hippocampus that was accompanied by hippocampal atrophy. The vascular changes were not congophilic. Yet, despite the lack of congophilia, penetrating vessels at the cortical surface were often abnormal morphologically and microhemorrhages sometimes occurred. Altered immunostaining of blood vessels with basement membrane-associated antigens was an early feature of the microangiopathy and was associated with thickening of the vascular basal laminae and endothelial cell alterations that were visible ultrastructurally. Interestingly, although the FAD-mutant transgene was expressed in neurons in both lines of mice, there was no detectable expression in vascular endothelial cells or glial cells. These studies thus have implications for the role of neuronal to vascular signaling in the pathogenesis of the vascular pathology associated with AD.

Arginase and vascular aging

Vascular and associated ventricular stiffness is one of the hallmarks of the aging cardiovascular system. Both an increase in reactive oxygen species production and a decrease in nitric oxide (NO) bioavailability contribute to the endothelial dysfunction that underlies this vascular stiffness, independent of other age-related vascular pathologies such as atherosclerosis. The activation/upregulation of arginase appears to be an important contributor to age-related endothelial dysfunction by a mechanism that involves substrate (L-arginine) limitation for NO synthase (NOS) 3 and therefore NO synthesis. Not only does this lead to impaired NO production but also it contributes to the enhanced production of reactive oxygen species by NOS. Although arginase abundance is increased in vascular aging models, it appears that posttranslational modification by S-nitrosylation of the enzyme enhances its activity as well. The S-nitrosylation is mediated by the induction of NOS2 in the endothelium. Furthermore, arginase activation contributes to aging-related vascular changes by mechanisms that are not directly related to changes in NO signaling, including polyamine-dependent vascular smooth muscle proliferation and collagen synthesis. Taken together, arginase may represent an as yet elusive target for the modification of age-related vascular and ventricular stiffness contributing to cardiovascular morbidity and mortality.

Age‐related differences in insulin‐like growth factor‐1 receptor signaling regulates Akt/FOXO3a and ERK/Fos pathways in vascular smooth muscle cells

Advanced age is a major risk factor for atherosclerosis, but how aging per se influences pathogenesis is not clear. Insulin-like growth factor-1 receptor (IGF-1R) promotes aortic vascular smooth muscle cell (VSMC) growth, migration, and extracellular matrix formation, but how IGF-1R signaling changes with age in VSMC is not known. We previously found age-related differences in the activation of Akt/FOXO3a and ERK1/2 pathways in VSMC, but the upstream signaling remains unclear. Using explanted VSMC from Fischer 344/Brown Norway F1 hybrid rats shown to display age-related vascular pathology similar to humans, we compared IGF-1R expression in early passages of VSMC and found a constitutive activation of IGF-1R in VSMC from old compared to young rats, including IGF-1R expression and its tyrosine kinase activity. The link between IGF-1R activation and the Akt/FOXO3a and ERK pathways was confirmed through the induction of IGF-1R with IGF-1 in young cells and attenuation of IGF-1R with an inhibitor in old cells. The effects of three kinase inhibitors: AG1024, LY294002, and TCN, were compared in VSMC from old rats to differentiate IGF-1R from other upstream signaling that could also regulate the Akt/FOXO and ERK pathways. Genes for p27kip-1, catalase and MnSOD, which play important roles in the control of cell cycle arrest and stress resistance, were found to be FOXO3a-targets based on FOXO3a-siRNA treatment. Furthermore, IGF-1R signaling modulated these genes through activation of the Akt/FOXO3a pathway. Therefore, activation of IGF-1R signaling influences VSMC function in old rats and may contribute to the increased risk for atherosclerosis.

Collateral function is impaired in aged F344 × BN rats with aortic pathology

Introduction: This study was performed to determine if hindlimb collateral function is impaired in a rat model which develops age-related vascular pathology similar to that observed in humans. Methods: Rats aged 6 (n = 6) and 24 (n = 6) months were studied. Under pentobarbital anesthesia, iliac artery blood flow was measured before and during occlusion of the femoral artery. The thoracic aorta, abdominal aorta, iliac arteries, and femoral arteries were harvested after perfusion fixation with paraformaldehyde and subsequently plastic embedded, sectioned, and stained. Results: Prior to occlusion, iliac flows were 3.0 ± 0.01 mL/min and 3.5 ± 0.02 mL/min respectively in 6 and 24 month old rats. After occlusion in the young rats, flow dropped initially by 0.8 ± 0.01 mL/min and then recovered by 0.7 ± 0.02 mL/min, essentially reaching pre-occlusion values. In 24 month old animals, flow decreased initially by 0.9 ± 0.01 mL/min but only recovered 0.4 ± 0.01 mL/min (p < 0.05). Intimal thickening was apparent only in the thoracic aorta of 24 month old animals. Conclusions: The increase in iliac artery blood flow after femoral artery occlusion reflects dilation of collateral vessels. The reduced compensation in older animals suggests that flow-dependent collateral dilation is reduced. This is consistent with studies which have demonstrated a progressive increase in endothelial dysfunction with aging. These observations together with the aortic pathology are consistent with the hypothesis that vascular aging not only promotes large vessel pathology, but also suppresses the capacity for compensation such as collateral dilation.

Venous collagenosis and arteriolar tortuosity in leukoaraiosis

Leukoaraiosis (LA), an age-related white matter degeneration, is thought to be caused by chronic ischemia. To understand the pathogenesis of LA, we studied the pathology, particularly of the blood vessels, in 186 brains [84 of them with magnetic resonance imaging (MRI)] over the past 10 years. With normal aging, there is gradual thickening of the walls of periventricular veins and venules with collagen subtypes I and III. This venous collagenosis (VC) was increased in brains with LA. Occasionally, LA lesions are not periventricular, but nearer the cortex. In such cases, the most severe VC occurs in the LA lesion rather than near the ventricle. Therefore, LA and VC are not independent degenerative processes coincidentally found near the ventricles, and although damage to the ependyma could be a cause of VC, it cannot be the only cause. Whether VC precedes LA is unknown, but our experience suggests that severe VC is usually accompanied by LA. Arteriolar tortuosity, another age-related vascular pathology, is common in LA. Our thick celloidin sections show three-dimensional views of tortuous arterioles. The tortuosity is much more severe in the white matter and there is considerable loss of parenchyma around them. Staining for collagen IV in the basal lamina reveals tortuous vessels in an “empty bag” that represents the limits of the surrounding parenchyma. These enlarged perivascular spaces correspond to état criblé. The demyelination in LA lesions is accompanied by loss of cells, mostly oligodendrocytes. In studies of apoptosis in LA, we found increased apoptosis within the lesion compared to the surrounding white matter. In conclusion, our studies support the concept that LA results from chronic ischemia due to age-related vascular pathology.

Aortic calcification produced by vitamin D3 plus nicotine.

Calcification of the elastic arteries of the young rat by treatment with vitamin D and nicotine (VDN) has been proposed as an animal model of arterial calcification associated with age and age-related vascular pathology in man. The calcium-binding protein, S-100, which is found in human atherosclerotic lesions was associated with medial calcification of the aorta in VDN rats, especially in cases of severe calcification. Calcification (total calcium content: 366 +/- 87, n = 12 in VDN vs. 24 +/- 2 micromol g(-1) aortic dry weight in controls, n = 13) involved elastocalcinosis leading to elastolysis as revealed by a fall in the amount of desmosine and isodesmosine in the aortic wall (266 +/- 17 and 254 +/- 15 in VDN vs. 655 +/- 56 and 588 +/- 30 microg g(-1) aortic dry weight in controls). The decrease in elastin was associated with an increase in the stiffness of the aortic wall (elastic modulus: 15.1 +/- 1.8 in VDN vs. 6.7 +/- 0.5 10(6) dyn cm(-2) in controls), an increase in end-systolic stress (central systolic aortic pressure: 152 +/- 6 in VDN vs. 136 +/- 2 mm Hg in controls) (at a normotensive mean pressure level) and left ventricular hypertrophy (heart weight/body weight 2.51 +/- 0.10 in VDN vs. 2.24 +/- 0.07 g kg(-1) in controls). In conclusion, the mechanisms and consequences of aortic calcification in VDN show several similarities with calcification occurring in human athero- and arteriosclerosis.