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Endothelial cell dysfunction is a complex process involving various causes, early and late events, and subsequent consequences. This review provides an overview of each aspect and outlines therapeutic interventions targeting these stages. Causes of endothelial dysfunction encompass a spectrum of risk factors including hypertension, diabetes, smoking, obesity, inflammation, oxidative stress, and genetic predispositions. Early events such as endothelial activation, inflammatory response, and dysregulated vasomotor tone precede late events like oxidative stress, endothelial apoptosis, and microvascular rarefaction. The consequences include endothelial remodelling, neovascularization, organ dysfunction, and clinical manifestations, highlighting the diverse impacts across multiple systems. While depicted linearly, the progression of endothelial dysfunction is dynamic, influenced by various factors such as the underlying cause and affected vascular bed. Understanding these dynamics is crucial for tailoring therapeutic interventions, ranging from lifestyle modifications to targeted therapies, to address the underlying causes and effects effectively. Here we provide comprehensive understanding of endothelial cell dysfunction that is essential for developing strategies to mitigate the impact of this dysregulation on health and cardiovascular diseases progression.

Vascular aging encompasses structural and functional changes in the vasculature, significantly contributing to cardiovascular diseases, which are the leading cause of death globally. The incidence and prevalence of these diseases increase with age, with most morbidity and mortality attributed to myocardial infarction and stroke. Diagnosing and intervening in vascular aging while understanding the mechanisms behind age-induced vascular phenotypic and pathophysiological alterations offers the potential for delaying and preventing cardiovascular mortality in an aging population. This review delves into various aspects of vascular aging by examining age-related changes in arterial health at the cellular level, including endothelial dysfunction, cellular senescence, and vascular smooth muscle cell transdifferentiation, as well as at the structural level, including arterial stiffness and changes in wall thickness and diameter. We also explore aging-related changes in perivascular adipose tissue deposition, arterial collateralization, and calcification, providing insights into the physiological and pathological implications. Overall, aging induces phenotypic changes that augment the vascular system’s susceptibility to disease, even in the absence of traditional risk factors, such as hypertension, diabetes, obesity, and smoking. Overall, age-related modifications in cellular phenotype and molecular homeostasis increase the vulnerability of the arterial vasculature to structural and functional alterations, thereby accelerating cardiovascular risk. Increasing our understanding of these modifications is crucial for success in delaying or preventing cardiovascular diseases. Non-invasive techniques, such as measuring carotid intima-media thickness, pulse wave velocity, and flow-mediated dilation, as well as detecting vascular calcifications, can be used for the early detection of vascular aging. Targeting specific pathological mechanisms, such as cellular senescence and enhancing angiogenesis, holds promise for innovative therapeutic approaches.

Preeclampsia, a systemic vascular disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation, is the leading cause of maternal and perinatal morbidity and mortality. Maternal endothelial dysfunction caused by placental factors has long been accepted with respect to the pathophysiology of preeclampsia. Over the past decade, increased production of placental antiangiogenic factors has been identified as a placental factor leading to maternal endothelial dysfunction and systemic vascular dysfunction. This review summarizes the recent advances in understanding the molecular mechanisms of endothelial dysfunction caused by placental antiangiogenic factors, and the novel clinical strategies based on these discoveries.

Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.

Vascular dysfunction is associated with onset of cardiovascular disease (CVD). Its effect is reflected as temperature change on the skin. The aim of this work was to test the potential of thermal imaging as cost effective screening tool for prediction of CVD. Thermal imaging of various parts of the subject (N = 80, male/female =44/36, aged 25-75 years) was done using noncontact infrared (IR) camera. In each subject, total cholesterol (TC; mg/dl) and high-density lipoprotein (HDL, mg/dl) were measured according to standard biochemical analysis. Based on National Cholesterol Education Program ATP III criteria, subject with known CVD (N = 16) and age- and sex- matched normal subjects (N = 21) were included in the study. The average surface temperature of various parts from head to toe was calculated and statistical analysis was performed between the groups. In the total population (N = 37), correlation study shows TC (mg/dl) was correlated with measured surface temperature of the following regions: Temporal left (r = −0.316) and right (r = −0.417), neck left (r = 0.347) and right (r = −0.410), and hand left (r = 0.387). HDL (mg/dl) was found to be correlated with measured surface temperature of the following regions: Temporal left (r = 0.445) and right (r = 0.458), hand left (r = −0.470), and foot anterior left (r = −0.332) and right (r = −0.336). Temperature asymmetry was more significant in upper extremity in CVD group. Using the surface temperature, regression models were calculated for noninvasive estimation of TC and HDL. The predictive ability of measured surface temperature for TC and HDL was 60%. The model for noninvasive estimation gave sensitivity and specificity value of 79 and 83% for TC and 78 and 81% for HDL, respectively. Thus, the surface temperature can be one of the screening tools for prediction of CVD. The limitation of the present study is also discussed under future work.

Purpose of ReviewMetabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver that occurs in the majority of patients in combination with metabolic dysfunction in the form of overweight or obesity. In this review, we highlight the cardiovascular complications in MAFLD patients as well as some potential mechanisms linking MAFLD to the development of cardiovascular disease and highlight potential therapeutic approaches to treating cardiovascular diseases in patients with MAFLD.Recent FindingsMAFLD is associated with an increased risk of cardiovascular diseases (CVD), including hypertension, atherosclerosis, cardiomyopathies, and chronic kidney disease. While clinical data have demonstrated the link between MAFLD and the increased risk of CVD development, the mechanisms responsible for this increased risk remain unknown.SummaryMAFLD can contribute to CVD through several mechanisms including its association with obesity and diabetes, increased levels of inflammation, and oxidative stress, as well as alterations in hepatic metabolites and hepatokines. Therapies to potentially treat MAFLD-induced include statins and lipid-lowering drugs, glucose-lowering agents, antihypertensive drugs, and antioxidant therapy.

Age-related macular degeneration (AMD) is a common irreversible ocular disease characterized by vision impairment among older people. Many risk factors are related to AMD and interact with each other in its pathogenesis. Notably, oxidative stress and choroidal vascular dysfunction were suggested to be critically involved in AMD pathogenesis. In this review, we give an overview on the factors contributing to the pathophysiology of this multifactorial disease and discuss the role of reactive oxygen species and vascular function in more detail. Moreover, we give an overview on therapeutic strategies for patients suffering from AMD.

Placental pathology is associated with major pregnancy disorders and the concept of the Great Placental Syndromes encompasses disorders of placentation, such as preeclampsia with and without fetal growth restriction, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and placental abruption. Preeclampsia is divided between the early and late onset variety and placental dysfunction is a central feature in the pathogenesis of both. In the early onset type, syncytiotrophoblastic stress seems to be related to an inherent defect of the trophoblast. Vascular protection of early placental development is replaced by vascular dysfunction. In late onset preeclampsia, maternal factors, such as genotypic predisposition to endothelial disease, and an impairment of antioxidant defence with a limited capacity of the maternal clearing system to cope with the increasing charge of apoptotic cell debris, are at the center of pathogenesis. Syncytiotrophoblastic stress in late pregnancy has been related to molecular senescence and late onset preeclampsia may be viewed as an exaggeration of normal placental ageing.

Objectives: To evaluate nitric oxide (NO)-mediated vascular dysfunction in patients with Systemic Sclerosis (SSc) compared to age- and sex-matched healthy controls through passive leg movement (PLM).   Materials and Methods: Twenty-one patients and twenty-one controls were enrolled. PLM was performed in a seated position, and blood flow (BF) was measured at the right common femoral artery (CFA), distal to the inguinal ligament and approximately 2 cm from the femoral bifurcation, by assessing flow velocity and vessel diameter. Baseline BF, peak flow (hyperaemia) during PLM, and the area under the curve (AUC) of BF over time were calculated. Patients were stratified according to phenotype (limited: lcSSc; diffuse: dcSSc), disease complications, and ongoing therapies.   Results: The mean disease duration was 16.2 years (SD ±9.78). Fifteen patients (71%) had lcSSc. The most frequent autoantibodies were anti-centromere (47%) and anti-Scl70 (43%). Nine patients (43%) had a history of digital ulcers (DU), eight (38%) had pulmonary arterial hypertension (PAH), and eleven (52%) had interstitial lung disease (ILD). Seventeen patients (81%) were on vasoactive therapy and eight were taking immunosuppressive treatment (Table 1). At rest, CFA diameter and baseline BF were not significantly different between groups (p=0.14 and p=0.56, respectively). Both groups exhibited a PLM-induced response. Peak BF was significantly reduced in SSc patients (467.7 vs 552.5; p=0.038), as well as change from baseline (p=0.005). The AUC was also significantly lower in patients (p=0.01) (Figure 1). No differences were observed between lcSSc and dcSSc in terms of peak flow (p=0.34) or AUC (p=0.3). A higher modified Rodnan skin score (mRSS) correlated with a smaller CFA diameter (p=0.001). The presence of DU history did not affect the hyperaemic response (p=0.65). Patients with PAH showed a slightly higher peak flow (p=0.05), likely related to vasoactive therapies. No correlation was found between PLM-induced hyperaemia and vasoactive treatments. Patients on statins had significantly lower baseline BF compared to those not receiving statins (p=0.03), possibly related to the role of statins on endothelial function.   Conclusions: PLM-induced hyperaemia is significantly reduced in SSc, highlighting the role of NO-mediated endothelial dysfunction in this disease, regardless of phenotype. PLM proves to be a valid technique for evaluating microvascular impairment in SSc. However, the absence of correlations between PLM response and drugs used, suggests the need for new endothelial-targeted drugs aimed at reversing vascular damage. Further studies are warranted to better define the role of PLM in SSc and its potential applications in clinical practice and therapeutic evaluation.