Endothelium, Nitric Oxide, and Atherosclerosis: From Basic Mechanism to Clinical Implications

La poursuite de l'integration de fonctions toujours plus complexes au sein d'un meme circuit constitue un des principaux enjeux de la microelectronique. L'integration tridimensionnelle par empilement de circuits (3D stacking) constitue une voie prometteuse pour y parvenir. Elle permet notamment de depasser certaines limitations atteintes par les circuits actuels, plus particulierement dans les circuits pour lesquelles les donnees sont distribuees et qui necessitent des bandes passantes importantes. Neanmoins, a ce jour, tres peu de travaux ont montre les avantages de l'integration 3D, en particulier ceux s'appuyant sur des resultats experimentaux et de circuits concrets notamment dans le domaine des imageurs. Le present travail de these a eu pour objectif d'exploiter la technologie 3D dans le cadre des capteurs d'images et depasser la preuve de concept presentee dans l'etat de l'art afin d'apporter une analyse concrete des apports de cette technologie dans le domaine des imageurs visibles. Nous avons identifie, d'une part l'extension de dynamique qui requiert un traitement proche pixel, d'autre part la compression locale, destinee a adresser les problemes d'integrite du signal, bande passante et consommation qui deviennent critiques avec l'augmentation des formats des imageurs. Ce choix permet d'apporter une reponse a la limitation de la dynamique des capteurs d'images 2D actuels, tout en gardant une architecture classique des pixels et en adressant le probleme de la reduction de la quantite de donnees a transmettre. Une nouvelle methode de codage flottant par groupe de pixels a ete proposee et implementee. Le principe s'appuie sur l'adaptation du temps d'integration par groupe de pixels via l'application d'un exposant commun au groupe. Le temps d'integration est ajuste a l'image suivante. Un premier niveau de compression est ainsi realise par le codage mantisse-exposant propose. L'implementation de cette technique a ete validee sur un demonstrateur 2D au detriment de pixels sacrifies aveugles de chaque groupe de pixels, comportant l'electronique de generation des signaux de commande de la HDR. La technique d'extension de dynamique proposee est suivie d'une compression a base de DCT (Discrete Cosine Transform} permettant de reduire le flux de donnees en sortie de la puce imageur. Les deux niveaux de compression permettent d'atteindre des taux de compression eleves allant jusqu'a 93% en maintenant un PSNR de 30dB et une qualite d'image acceptable pour des post-traitements. Une etude theorique de l'apport de l'integration 3D en termes de consommation a ete elaboree. Enfin, un demonstrateur 2D a ete realise en technologie CMOS 180 nm en vue de valider l'architecture grande dynamique proposee. L'utilisation de la technologie 3D, dans la suite des travaux, permet l'implementation d'une boucle courte, devenue possible grâce aux interconnexions verticales sans sacrifier des pixels morts. Le traitement local proche du pixel et la reduction de la latence, du flux de donnees et de la consommation sont les apports majeurs de l'integration 3D etudies dans ce travail

Previous studies have indicated that there are large sex differences in the incidence of hypertension, and the role of androgens in enhancing the risk of cardiovascular disease is well recognized.1,2 However, the mechanisms by which androgens increase blood pressure are poorly understood. Recent studies have demonstrated that androgen-sensitive forms of hypertension are associated with increased production of 20-hydroxyeicosatetranoic acid (20-HETE) in the kidney and the vasculature.3 However, the role of 20-HETE in this form of hypertension has not been established, because this pathway has both prohypertensive and antihypertensive actions.4 At the level of the renal tubule, upregulation of the formation of 20-HETE inhibits sodium transport and opposes the development of hypertension, whereas in the vasculature, 20-HETE is a potent vasoconstrictor that promotes hypertension. The study of Singh et al5 in the current issue explores the role of 20-HETE in the development of endothelial dysfunction and hypertension in rats chronically treated with dihydrotestosterone. The results indicate that that the expression cytochrome P450 4A protein and the production of 20 HETE increase in renal arteries of rats treated with dihydrotestosterone. The increase in vascular 20-HETE production is because of upregulation of the expression of the cytochrome P450 4A8 isoform. The development of hypertension in these studies was associated with the development of endothelial dysfunction, as reflected by an impaired vasodilator response to acetylcholine, increased expression of the gp-91 …

Endothelial dysfunction in cardiovascular diseases

The insulin resistance syndrome (IRS) is considered to be a new target of risk-reduction therapy. The IRS is a cluster of closely associated and interdependent abnormalities and clinical outcomes that occur more commonly in insulin-resistant/hyperinsulinemic individuals. This syndrome predisposes individuals to type 2 diabetes, cardiovascular diseases, essential hypertension, certain forms of cancer, polycystic ovary syndrome, nonalcoholic fatty liver disease, and sleep apnea. In patients at high risk for cardiovascular diseases, endothelial dysfunction is observed in morphologically intact vessels even before the onset of clinically manifest vascular disease. Indeed, there are several lines of evidence that indicate that endothelial function is compromised in situations where there is reduced sensitivity to endogenous insulin. It is well established that a decreased bioavailability of nitric oxide (NO) contributes to endothelial dysfunction. Furthermore, NO may modulate insulin sensitivity. Activation of NO synthase (NOS) augments blood flow to insulin-sensitive tissues (i.e. skeletal muscle, liver, adipose tissue), and its activity is impaired in insulin resistance. Inhibition of NOS reduces the microvascular delivery of nutrients and blunts insulin-stimulated glucose uptake in skeletal muscle. Furthermore, induction of hypertension by administration of the NOS inhibitor NG-monomethyl-L-arginine is also associated with insulin resistance in rats. Increased levels of asymmetric dimethylarginine (ADMA) are associated with endothelial vasodilator dysfunction and increased risk of cardiovascular diseases. An intriguing relationship exists between insulin resistance and ADMA. Plasma levels of ADMA are positively correlated with insulin resistance in nondiabetic, normotensive people. New basic research insights that provide possible mechanisms underlying the development of insulin resistance in the setting of impaired NO bioavailability will be discussed.

Coronary Artery Disease (CAD) and erectile dysfunction (ED) are cardiovascular complications frequently occurring in patients with diabetes, obesity, and dyslipidemia. All these metabolic disorders are characterized by insulin resistance, defined as decreased sensitivity and/or responsiveness to metabolic actions of insulin promoting glucose disposal. Insulin resistance is not only a hallmark of metabolic abnormalities, but also a prominent feature of haemodynamic disorders. Indeed, insulin-stimulated release of endothelial factors takes part into the physiological regulation of vascular function, and altered insulin actions may profoundly affect cardiovascular homeostasis under metabolic derangement. The signpost of impaired vascular reactivity is endothelial dysfunction, a condition in which the endothelium loses its physiological ability to produce the vasodilator nitric oxide (NO). A number of molecular, cellular, physiological, and clinical studies have indicated that insulin resistance may impair NO release and damage endothelial function through several patho-physiological mechanisms reciprocally interconnected. Although considered the earliest marker of impaired vascular health, endothelial dysfunction is initially asymptomatic; additional changes in the vessel structure are usually required before vascular complications manifest. Nevertheless, endothelial dysfunction may become clinically evident when endothelial-mediated relaxation is necessary and sufficient to exert a specific effect. ED may be the first expression of endothelial dysfunction, and therefore represents a sentinel event in the clinical appearance of silent CAD. Thus, insulin resistance triggers endothelial dysfunction, and endothelial dysfunction may manifest as ED long before CAD or other vascular complications become clinically evident. This review briefly outlines the main characteristics of endothelial function and dysfunction, and describes the signaling pathways involved in cardiovascular actions of insulin under physiological and pathological conditions. Moreover, potential cellular and molecular mechanisms linking insulin resistance to early CAD-ED detection are also illustrated.

For several decades, the vascular endothelium was considered a unicellular layer acting as a semipermeable membrane between the blood and the interstitium. Recently, it has been demonstrated that the endothelium performs a large range of important biological functions, participating in several metabolic and regulatory pathways. Along with long-known specialized functions like gaseous exchange in the pulmonary circulation and phagocytosis in the hepatic and splenic circulation, the vascular endothelium performs universal roles in the circulation that include participation in thrombosis and thrombolytic control, vascular growth, platelet and leukocyte interactions with the vascular wall, and vasomotor tone. The study of endothelium-dependent vasomotor reactivity has produced over the years, scientific evidence fundamental for the understanding of the endothelium’s role in physiological and pathological situations. In 1977, Moncada et al, published the first report indicating that the endothelium plays a central role in the control of vascular tone via the production of vasoactive substances . In 1980, Furchgott and Zawadzki 2 demonstrated in an experimental preparation of the rabbit aorta, the obligatory role played by endothelial cells in vascular relaxation in response to effectors like acetylcholine, and postulated the existence of a vascular relaxing factor derived from the endothelium. In 1987, two research groups, lead by Ignarro et al , and by Palmer et al , demonstrated that the relaxing factor derived from the endothelium was nitric oxide, an odorless gas until then considered as a mere pollutant. Endothelial dysfunction was first characterized in humans in 1986 by Ludmer et al, 5 who demonstrated that atherosclerotic coronary arteries contracted in response to intracoronary infusion of acetylcholine, while normal coronaries showed dilatation. In 1992, endothelial dysfunction was documented by Celermajer et al 6 in children and otherwise healthy young adults with risk factors for atherosclerosis. Under physiological conditions, the endothelium keeps a reduced vasomotor tone, prevents leukocyte and platelet adhesion, and inhibits the proliferation of vascular smooth muscle cells. In contrast, endothelial dysfunction appears to play a pathogenic role in the initial development of atherosclerosis 7-9 and of unstable coronary syndromes , being associated with atherosclerotic disease risk factors , and being present even before vascular involvement becomes evident . Recent clinical studies have demonstrated that some drugs well known to reduce the incidence of cardiovascular events, improve endothelial function . On the other hand, clinical interventions like the continuous administration of organic nitrates and percutaneous coronary interventions may be associated with adverse effects on the vascular endothelium. In the present article, we will discuss vascular endothelial function versus dysfunction, and their impact on cardiovascular disease, in particular atherosclerosis.

Functional assessment of the blood pressure waveform helps us to obtain an estimation of the arterial stiffness or its converse, arterial elasticity.1 Several epidemiological studies have clearly demonstrated that arterial stiffness is a significant predictor of cardiovascular disease incidence in the general population.2 There is clear evidence now that decreased arterial elasticity or increased arterial stiffness in normotensive and prehypertensive subjects induces increased risk for the development of arterial hypertension. In vitro and in vivo experiments have shown that the vascular endothelium plays a crucial role in vascular tone and consequently in arterial stiffness. However, there are no data available regarding the endothelial pathways involved in the adaptation of arterial mechanics during changes in blood flow. The elegant study by Bellien et al3 in this issue of Hypertension studied the endothelial pathways involved in the adaption of arterial mechanics during changes in blood flow. Besides identifying the “endothelial-derived relaxing factor” nitric oxide (NO) as important in this biological process, a unique aspect found in their study was the “endothelial-hyperpolarizing factor” EDHF. Endothelium-dependent relaxation/vasodilation in response to neurohumoral mediators and physical forces, such as the shear stress caused by blood flow, is generally attributed to the release of NO and/or prostacyclin. However, NO and prostacyclin cannot fully explain these endothelium-mediated vasodilator responses. The relaxations observed in the presence of NO synthase and cyclooxygenase inhibitors are often associated with hyperpolarization of the vascular smooth …

The vascular system is essential for organ function and tissue homeostasis, with endothelial cells regulating vascular tone, permeability, angiogenesis, and blood interactions.Disruption of this balance causes endothelial dysfunction, a central driver of cardiovascular and metabolic diseases. This is aggravated by maladaptive phenotypic transitions, particularly endothelial-to-mesenchymal transition (EndMT), which, though beneficial in repair, promotes fibrosis, remodeling, and plaque instability when dysregulated, contributing to atherosclerosis, diabetes, and hypertension (Kovacic et al., 2019). Understanding these transitions remains a challenge. This Research Topic explores the interplay between endothelial dysfunction and vascular cell phenotypes in disease progression (Figure 1).Within the context of atherosclerosis, endothelial dysfunction represents an initiating and central event, as highlighted by Yang et al., who offer an integrative perspective bridging traditional pharmacotherapy with emerging novel therapeutic approaches. Their review emphasizes how endothelial and vascular cell phenotypic changes drive the disease process, through EndMT-derived fibroblast accumulation (Brokopp et al., 2011), extracellular matrix deposition and inflammation (Cheng et al., 2015), and vascular smooth muscle cell (VSMC) switching (Chappell et al., 2016). Yang et al. illustrate how targeting maladaptive cell states through statins, renin-angiotensin system inhibitors, microRNAs, and reprogramming strategies may represent a paradigm shift for long-term vascular health.A similar emphasis on endothelial dysfunction is evident in the context of diabetes.Here, Liu et al. expand on the multifactorial pathways, including oxidative stress, insulin resistance, and chronic hyperglycemia, that converge to impair endothelial cell function (Shah, Brownlee, 2016). By showing how these stressors reduce nitric oxide bioavailability, disrupt intercellular junctions, and trigger epigenetic modifications, their review underscores the endothelial cell as the primary target of diabetic vascular damage. Importantly, they also highlight how therapeutic strategies, including compounds from traditional Chinese medicine, may help preserve or restore endothelial function, positioning these cells as central targets for reducing cardiovascular risk in diabetes. (Moschetti et al., 2022;Cecere et al., 2024), further reinforcing the idea that vascular pathology emerges from a convergence of endothelial injury, phenotypic transitions, and immune activation.These studies illustrate the role of endothelial dysfunction and vascular cell phenotypic transitions in a wide spectrum of cardiovascular diseases. Endothelial cells, along with phenotypically plastic of vascular cells, constitute both key drivers of vascular injury and promising therapeutic targets. These findings highlight the importance of moving beyond symptom control to strategies that restore vascular homeostasis by correcting dysfunctional cellular states, thereby opening the door to transformative therapies for cardiovascular diseases.

Purpose of ReviewHypertension is either a cause or a consequence of the endothelial dysfunction and a major risk factor for cardiovascular disease (CVD). In vitro and in vivo studies established that microRNAs (miRNAs) are decisive for endothelial cell gene expression and function in various pathological conditions associated with CVD.This review provides an overview of the miRNA role in controlling the key connections between endothelial dysfunction and hypertension.Recent FindingsHerein we summarize the present understanding of mechanisms underlying hypertension and its associated endothelial dysfunction as well as the miRNA role in endothelial cells with accent on the modulation of renin-angiotensin-aldosterone-system, nitric oxide, oxidative stress and on the control of vascular inflammation and angiogenesis in relation to endothelial dysfunction in hypertension. In particular, latest insights in the identification of endothelial-specific microRNAs and their targets are added to the understanding of miRNA significance in hypertension.SummaryThis comprehensive knowledge of the role of miRNAs in endothelial dysfunction and hypertension and of molecular mechanisms proposed for miRNA actions may offer novel diagnostic biomarkers and therapeutic targets for controlling hypertension-associated endothelial dysfunction and other cardiovascular complications.

Evidence continues to accumulate on the importance of EDHF in vascular homeostasis (Feletou & Vanhoutte, 2001; Golding et al. 2002; Selemidis & Cocks, 2002). A number of physical and chemical stimuli can activate endothelial cells to produce and release vasodilator substances including nitric oxide and prostacyclin. In some blood vessels activation of the endothelium causes hyperpolarization of both endothelium and underlying smooth muscle cells, leading to vasodilatation. The chemical nature of EDHF as well as the contribution of direct transfer of hyperpolarizing current from endothelial cells to smooth muscle cells has been an object of intense investigation ever since the original observation of endothelium-dependent hyperpolarization by Feletou and Vanhoutte in 1988. Potassium ions, cytochrome-P450-derived epoxyeicosatrienoic acids (EETs), and hydrogen peroxide have been proposed as possible EDHFs (Feletou & Vanhoutte, 2001). Spreading of hyperpolarizing current via myoendothelial junctions is another key mechanism of endothelium-dependent hyperpolarization (Feletou & Vanhoutte, 2001). Despite remaining uncertainties regarding the exact nature of EDHF, consensus has been reached that initiation of hyperpolarization is dependent on activation of Ca2+-sensitive K+ (KCa) channels in endothelial cells. Apamin and charybdotoxin selectively inhibit KCa channels. These compounds are valuable pharmacological tools needed for the characterization of the role of EDHF in control of vascular function. The concept of vascular endothelial dysfunction emerged from recognition of the critical role endothelium plays in the regulation of vasomotor function, inflammation, blood coagulation, and angiogenesis. Dysfunctional endothelium favours vasoconstriction, smooth muscle cell proliferation, platelet aggregation, and white blood cell adhesion, and may impair angiogenesis. Numerous studies suggest that loss of the biological activity of nitric oxide and/or its biosynthesis is the central mechanism responsible for endothelial dysfunction (Katusic, 2001). The exact mechanisms responsible for endothelial dysfunction in arteries exposed to chronic hypertension are not completely understood, but may involve chemical antagonism between superoxide anions and nitric oxide and functional antagonism of nitric oxide-mediated vasodilatation due to release of endothelium-derived contracting factor(s) (Katusic & Shepherd, 1991; Vanhoutte, 1996). The study by Sofola et al. (2002), reported in this issue of The Journal of Phsyiology, provides evidence that in hypertension induced by a high salt diet, EDHF may compensate for the loss of nitric oxide and preserve endothelium-dependent relaxations in response to acetylcholine in mesenteric resistance arteries. This observation supports the concept that EDHF may serve as an important compensatory mechanism in arteries exposed to hypertension. More importantly, this observation illustrates that, in diseased arteries, ‘normal’ endothelium-dependent relaxations in response to acetylcholine should not be interpreted as if there is no alteration in endothelial function. Analysis of the mechanism underlying endothelium-dependent relaxation is critical and can unmask endothelial dysfunction due to loss of nitric oxide. Increased vascular resistance is certainly one of the most important mechanisms responsible for the pathogenesis of hypertension. Emerging evidence strongly suggests that the relative contribution of EDHF to endothelial control of vasomotor function increases as the diameter of the blood vessel decreases (Golding et al. 2002). Although the exact role of EDHF in the pathogenesis of hypertension is not completely understood, it appears that localization of EDHF in small resistance arteries is an important mechanism designed to maintain normal vascular resistance. In contrast to nitric oxide, EDHF is not inactivated by oxidative stress. Nitric oxide acts locally whereas EDHF-induced vasodilatation may spread to remote segments of the arterial wall (Selemidis & Cocks, 2002). These characteristics may explain why EDHF can function as a back-up mechanism in vascular diseases associated with oxidative stress and subsequent loss of local homeostatic control mediated by nitric oxide. As acknowledged in the Discussion of the present study by Sofola and colleagues (2002), in mesenteric arteries acetylcholine is not the physiological stimulus for the release of nitric oxide or EDHF. It would certainly be interesting to know whether shear stress-induced vasodilatation is affected by hypertension and whether EDHF may play the same compensatory role as it does in endothelium-dependent relaxations in response to acetylcholine. Furthermore, the precise mechanism responsible for the compensatory effect of EDHF in salt-induced hypertension is unclear. Is it due to up-regulation of EDHF formation and/or release? Does hypertension change reactivity of smooth muscle cells to EDHF? Is there any change in the conductivity of hyperpolarization? Does a high salt diet affect the expression and function of the proteins involved in the formation of gap junctions and the propagation of hyperpolarization? Obviously these questions remain to be answered in future studies. A better understanding of EDHF and its ability to act as a compensatory mechanism may provide the basis for development of new therapeutic approaches to vascular endothelial dysfunction.

Oxidants and Endothelial Dysfunction

Background: Arsenic exposure from drinking water has been related to elevated risks of an array of cardiovascular disease, including hypertension, ischemic heart disease, and carotid atherosclerosis. Although mechanistic studies have suggested that arsenic promotes inflammatory activity and lead to endothelial dysfunction, epidemiologic studies that evaluate the associations of arsenic exposure with biomarkers for inflammation and endothelial dysfunction relevant to CVD are needed. Methods: We assessed the relationship between arsenic exposure, measured in both well water samples and urinary samples, and an arrays of makers for inflammation and endothelial dysfunction, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), soluble intracellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1), in serum samples collected from 669 participants aged 30 and above randomly selected from the Health Effects of Arsenic Longitudinal Study (HEALS), a population-based study in Araihazar, Bangladesh. Serum levels of markers were analyzed using xMap™ technology, with commercially available high-sensitivity kits from Linco/Millipore Research. Linear regression was conducted to evaluate association between arsenic exposure and each of the markers. Results/Conclusions: Ongoing data analyses suggest that arsenic exposure is positively related to levels of several markers for oxidative stress and inflammation relevant to CVD. This is the first large study on arsenic exposure and markers of vascular inflammation and endothelial dysfunction in cardiovascular disease (CVD), and the findings may suggest possible mechanisms by which arsenic may lead to CVD.

Intracoronary myocardial contrast echocardiography (MCE) can be used to guide the delivery of ethanol during nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. The echocardiographic contrast agent is injected immediately before the injection of ethanol, down the lumen of the inflated balloon that resides in the target septal coronary artery. This is the artery that supplies the area of the septum involved with the mitral leaflet(s) in causing dynamic outflow tract obstruction. MCE provides a direct visualization of the myocardial territory that should receive ethanol and consequently undergo infarction. In rare instances, the cannulated vessel does not supply the culprit septal segment(s) but supplies instead …

<i>Circulation:</i> Clinical Summaries

Nitric Oxide- and Heme-Independent Activation of Soluble Guanylate Cyclase Attenuates Peroxynitrite-Induced Endothelial Dysfunction in Rat Aorta