Inflammation as A Precursor of Atherothrombosis, Diabetes and Early Vascular Aging

Vascular disease was for a long time considered a disease of the old age, but it is becoming increasingly clear that a cumulus of factors can cause early vascular aging (EVA). Inflammation plays a key role in vascular stiffening and also in other pathologies that induce vascular damage. There is a known and confirmed connection between inflammation and atherosclerosis. However, it has taken a long time to prove the beneficial effects of anti-inflammatory drugs on cardiovascular events. Diabetes can be both a product of inflammation and a cofactor implicated in the progression of vascular disease. When diabetes and inflammation are accompanied by obesity, this ominous trifecta leads to an increased incidence of atherothrombotic events. Research into earlier stages of vascular disease, and documentation of vulnerability to premature vascular disease, might be the key to success in preventing clinical events. Modulation of inflammation, combined with strict control of classical cardiovascular risk factors, seems to be the winning recipe. Identification of population subsets with a successful vascular aging (supernormal vascular aging—SUPERNOVA) pattern could also bring forth novel therapeutic interventions.

Targeting Epigenetic Mechanisms in Vascular Aging

Environment, diseases, lack of exercise, and aged tendency of population have becoming crucial factors that induce vascular aging. Vascular aging is unmodifiable risk factor for diseases like diabetes, hypertension, atherosclerosis, and hyperlipidemia. Effective interventions to combat this vascular function decline is becoming increasingly urgent as the rising hospitalization rate caused by vascular aging-related diseases. Fortunately, recent transformative omics approaches have enabled us to examine vascular aging mechanisms at unprecedented levels and precision, which make our understanding of slowing down or reversing vascular aging become possible. Epigenetic viz. DNA methylation, histone modifications, and non-coding RNA-based mechanisms, is a hallmark of vascular aging, its deregulation leads to aberrant transcription changes in tissues. Epigenetics mechanisms by mediating covalent modifications to DNA and histone proteins, consequently, influence the sensitivity and activities of signaling pathways in cells and tissues. A growing body of evidence supports correlations between epigenetic changes and vascular aging. In this article, we will provide a comprehensive overview of epigenetic changes associated with vascular aging based on the recent findings with a focus on molecular mechanisms of action, strategies to reverse epigenetic changes, and future perspectives.

Ιmmunity, Vascular Aging, and Stroke

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.

Vascular Aging and Diseases: Molecular Mechanisms and Influences

Vascular aging plays an important role in the mortality of the elderly, but vascular aging can be dependent on other factors such as diseases. Various diseases such as Alzheimer, diabetes, thalassemia, and other diseases affect the mechanisms of vascular aging. It will harm the recovery process of these patients. There are methods for measuring vascular aging such as instrumental measurements and molecular methods. The best way to measure vascular aging is a combination of methods to determine the mechanism and cause of vascular aging. In this review article, we first summarize the various mechanisms of vascular aging and then discuss the effect of different disease on vascular aging.

Single-Cell Analysis Identify Transcription Factor BACH1 as a Master Regulator Gene in Vascular Cells During Aging

Vascular aging is a potent driver of cardiovascular and cerebrovascular diseases. Vascular aging features cellular and functional changes, while its molecular mechanisms and the cell heterogeneity are poorly understood. This study aims to 1) explore the cellular and molecular properties of aged cardiac vasculature in monkey and mouse and 2) demonstrate the role of transcription factor BACH1 in the regulation of endothelial cell (EC) senescence and its mechanisms. Here we analyzed published single-cell RNA sequencing (scRNA-seq) data from monkey coronary arteries and aortic arches and mouse hearts. We revealed that the gene expression of YAP1, insulin receptor, and VEGF receptor 2 was downregulated in both aged ECs of coronary arteries’ of monkey and aged cardiac capillary ECs of mouse, and proliferation-related cardiac capillary ECs were significantly decreased in aged mouse. Increased interaction of ECs and immunocytes was observed in aged vasculature of both monkey and mouse. Gene regulatory network analysis identified BACH1 as a master regulator of aging-related genes in both coronary and aorta ECs of monkey and cardiac ECs of mouse. The expression of BACH1 was upregulated in aged cardiac ECs and aortas of mouse. BACH1 aggravated endothelial cell senescence under oxidative stress. Mechanistically, BACH1 occupied at regions of open chromatin and bound to CDKN1A (encoding for P21) gene enhancers, activating its transcription in senescent human umbilical vein endothelial cells (HUVECs). Thus, these findings demonstrate that BACH1 plays an important role in endothelial cell senescence and vascular aging.

Longevity Factor FOXO3: A Key Regulator in Aging-Related Vascular Diseases

Forkhead box O3 (FOXO3) has been proposed as a homeostasis regulator, capable of integrating multiple upstream signaling pathways that are sensitive to environmental changes and counteracting their adverse effects due to external changes, such as oxidative stress, metabolic stress and growth factor deprivation. FOXO3 polymorphisms are associated with extreme human longevity. Intriguingly, longevity-associated single nucleotide polymorphisms (SNPs) in human FOXO3 correlate with lower-than-average morbidity from cardiovascular diseases in long-lived people. Emerging evidence indicates that FOXO3 plays a critical role in vascular aging. FOXO3 inactivation is implicated in several aging-related vascular diseases. In experimental studies, FOXO3-engineered human ESC-derived vascular cells improve vascular homeostasis and delay vascular aging. The purpose of this review is to explore how FOXO3 regulates vascular aging and its crucial role in aging-related vascular diseases.

Early Vascular Aging in Children With Type 1 Diabetes and Ambulatory Normotension

Background: Preliminary data suggest that target organ damage (TOD) and early vascular aging (EVA) may occur in children with normal blood pressure (BP).Objectives: To analyze TOD and EVA in normotensive (BP <95th percentile on ambulatory BP monitoring) type 1 diabetes children (T1D) in comparison to healthy controls (C).Subjects: 25 T1D aged 13.9 ± 2.6 years and 22 C aged 14.0 ± 3.4 years.Methods: We analyzed age- and height-related pulse wave velocity (PWV) Z-scores and expected PWV based on age, height, and mean arterial pressure (MAP). Expected vascular age based on measured PWV was calculated from pooled pediatric and adult PWV norms. Left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), and urinary albumin/creatinine ratio (ACR) were obtained as markers of TOD.Results: T1D and C groups did not differ in anthropometry, ambulatory, LVMI, and ACR. However, median age- and height-related PWV Z-scores were higher in T1D compared to C (1.08 vs. 0.57, p = 0.006; 0.78 vs. 0.36, p = 0.02, respectively). Mean (±SD) difference between measured and expected PWV was 0.58 ± 0.57 in T1D vs. 0.22 ± 0.59 in C, p = 0.02. The mean (±SD) difference between chronological and expected vascular age was 7.53 ± 7.74 years in T1D vs. 2.78 ± 7.01 years in C, p = 0.04.Conclusion: Increased arterial stiffness and increased intraindividual differences between expected and measured PWV as well as between chronological and expected vascular age indicate that EVA may develop in T1D children even at normal ambulatory BP levels.