Report on the 18th International Conference on Endothelin, October 11th - 14th 2023.

The 18th International Conference on Endothelin, co-organized by the International Advisory Board (IAB) on Endothelin and the Fondazione Internazionale Menarini, was held in Rome, Italy, on October 11th-14th, 2023. More than 100 attendees from all over the world participated in the conference, including trainees, early-career and established investigators from several European countries (Italy, France, Switzerland, Sweden, the Netherlands, Belgium, the United Kingdom (UK), Germany, the Czech Republic), USA, Canada, Japan, Australia, Brazil, China, Taiwan, and Indonesia.

Is endothelin targeting finally ready for prime time?

The endothelin family of peptides has long been recognized as a physiological regulator of diverse biological functions and mechanistically involved in various disease states, encompassing, among others, the cardiovascular system, the kidney, and the nervous system. Pharmacological blockade of the endothelin system, however, has encountered strong obstacles in its entry into the clinical mainstream, having obtained only a few proven indications until recently. This translational gap has been attributable predominantly to the relevant side effects associated with endothelin receptor antagonism (ERA), particularly fluid retention. Of recent, however, an expanding understanding of the pathophysiological processes involving endothelin, in conjunction with the development of new antagonists of endothelin receptors or adjustment of their doses, has driven a flourish of new clinical trials. The favorable results of some of them have extended the proven indications for ET targeting to a variety of clinical conditions, including resistant arterial hypertension and glomerulopathies. In addition, on the ground of strong preclinical evidence, other studies are ongoing to test the potential benefits of ERA in combination with other treatments, such as sodium-glucose co-transporter 2 inhibition in fluid retentive states or anti-cancer therapies in solid tumors. Furthermore, antibodies providing long-term blockade of endothelin receptors are under testing to overcome the short half-life of most small molecule endothelin antagonists. These efforts may yet bring new life to the translation of endothelin targeting strategies in clinical practice.

Variable dysregulation of circulating lipocalin-2 in different obese phenotypes: Association with vasodilator dysfunction.

BACKGROUND: Obesity is linked with heightened cardiovascular risk, especially when accompanied by metabolic abnormalities. Lipocalin (LCN) 2 and retinol-binding protein (RBP) 4, two members of the lipocalin family, may be upregulated in insulin resistance and atherosclerosis. We analyzed whether changes in circulating LCN2 and RBP4 in obese individuals relate with impaired vasodilator reactivity, an early stage in atherosclerosis. METHODS: Obese individuals (n = 165), without (n = 48) or with (n = 117) metabolic abnormalities, and lean subjects (n = 42) participated in this study. LCN2 and RBP4 were measured by Luminex assay. Endothelium-dependent and -independent vasodilation to acetylcholine and sodium nitroprusside, respectively, was assessed by strain-gauge plethysmography. RESULTS: Circulating LCN2 was higher in obese than in lean subjects (p < 0.001), whereas RBP4 was not different between the two groups (p = 0.12). The vasodilator responses to both acetylcholine and nitroprusside were impaired in obese individuals (p < 0.001 vs lean subjects), with no difference between those with metabolically healthy or unhealthy obesity (p > 0.05). In the whole population, vasodilator responses to acetylcholine (R = 0.23, p = 0.01) and nitroprusside (R = 0.38, p < 0.001) had an inverse, linear relationship with circulating LCN2; no correlation, by contrast, was observed between circulating RBP4 and vasodilator reactivity (both p > 0.05). In a subgroup of obese patients with diabetes (n = 20), treatment with metformin (n = 10) or pioglitazone (n = 10) did not modify circulating LCN2 and RBP4 or vascular reactivity (all p > 0.05). CONCLUSIONS: Circulating LCN2, but not RBP4, is higher in obese than in lean individuals. Interestingly, changes in LCN2 inversely relate to those in vasodilator function, thereby making this protein a potential biomarker for risk stratification in obesity.

Vasodilator Dysfunction in Human Obesity: Established and Emerging Mechanisms.

ABSTRACT: Human obesity is associated with insulin resistance and often results in a number of metabolic abnormalities and cardiovascular complications. Over the past decades, substantial advances in the understanding of the cellular and molecular pathophysiological pathways underlying the obesity-related vascular dysfunction have facilitated better identification of several players participating in this abnormality. However, the complex interplay between the disparate mechanisms involved has not yet been fully elucidated. Moreover, in medical practice, the clinical syndromes stemming from obesity-related vascular dysfunction still carry a substantial burden of morbidity and mortality; thus, early identification and personalized clinical management seem of the essence. Here, we will initially describe the alterations of intravascular homeostatic mechanisms occurring in arteries of obese patients. Then, we will briefly enumerate those recognized causative factors of obesity-related vasodilator dysfunction, such as vascular insulin resistance, lipotoxicity, visceral adipose tissue expansion, and perivascular adipose tissue abnormalities; next, we will discuss in greater detail some emerging pathophysiological mechanisms, including skeletal muscle inflammation, signals from gut microbiome, and the role of extracellular vesicles and microRNAs. Finally, it will touch on some gaps in knowledge, as well as some current acquisitions for specific treatment regimens, such as glucagon-like peptide-1 enhancers and sodium-glucose transporter2 inhibitors, that could arrest or slow the progression of this abnormality full of unwanted consequences.

Anti-Inflammatory and Proliferative Properties of Luteolin-7-O-Glucoside.

Flavonoids display a broad range of structures and are responsible for the major organoleptic characteristics of plant-derived foods and beverages. Recent data showed their activity, and in particular of luteolin-7-O-glucoside (LUT-7G), in reduction of oxidative stress and inflammatory mechanisms in different physiological systems. In this paper, we tried to elucidate how LUT-7G could exert both antioxidant and anti-inflammatory effects in endothelial cells cultured in vitro. Here, we showed that LUT-7G is able to inhibit the STAT3 pathway, to have an antiproliferative action, and an important antioxidant property in HUVEC cells. These properties are exerted by the flavone in endothelial through the transcriptional repression of a number of inflammatory cytokines and their receptors, and by the inhibition of ROS generation. ROS and STAT3 activation has been correlated with the production of oxysterols and other hydroxylated fatty acids, and they have been recognized important as players of atherogenesis and cardiocirculatory system diseases. The analysis of the general production pathway of these hydroxylated species, showed a strong decrease of cholesterol hydroxylated species such as 7-alpha-hydroxicholesterol, 7-beta-hydroxicholesterol by the treatment with LUT-7G. This confirms the anti-inflammatory properties of LUT-7G also in the endothelial district, showing for the first time the molecular pathway that verify previous postulated cardiovascular benefits of this flavone.

Intricacies of the endothelin system in human obesity: role in the development of complications and potential as a therapeutic target.

Activation of the vascular endothelin-1 (ET-1) system is a key abnormality in vascular dysfunction of human obesity, especially in patients developing complications, such as the metabolic syndrome, diabetes, and atherosclerosis. Vascular insulin resistance, an increased insulin-stimulated endothelial production of ET-1 combined with impaired nitric oxide availability, is the hallmark of obesity-related vasculopathy, but dysregulated adipokine release from obese adipose tissue may contribute to the predominance of ET-1-dependent vasoconstriction. ET-1, in turn, might determine unhealthy obese adipose tissue expansion, with visceral and perivascular adipose tissue changes driving the release of inflammatory cytokines and atherogenic chemokines. In addition, ET-1 might also play a role in the development of the metabolic complications of obesity. Studies have shown inhibition of lipoprotein lipase activity by ET-1, with consequent hypertriglyceridemia. Also, ET-1 in pancreatic islets seems to contribute to beta cell dysfunction, hence affecting insulin production and development of diabetes. Moreover, ET-1 may play a role in nonalcoholic steatohepatitis. Recent clinical trials using innovative design have demonstrated that antagonism of ET-type A receptors protects against some complications of obesity and diabetes, such as nephropathy. These findings encourage further investigation to evaluate whether targeting the ET-1 system could afford better protection against other consequences of the obesity epidemic.

Calcification biomarkers and vascular dysfunction in obesity and type 2 diabetes: influence of oral hypoglycemic agents.

Vascular aging in obesity and type 2 diabetes (T2D) is associated with progressive vascular calcification, an independent predictor of morbidity and mortality. Pathways for vascular calcification modulate bone matrix deposition, thus regulating calcium deposits. We investigated the association between biomarkers of vascular calcification and vasodilator function in obesity or T2D, and whether antidiabetic therapies favorably impact those markers. Circulating levels of proteins involved in vascular calcification, such as osteopontin (OPN), osteoprotegerin (OPG), regulated on activation, normal T cell expressed and secreted (RANTES), and fetuin-A were measured in lean subjects, individuals with metabolically healthy obesity (MHO), and patients with metabolically unhealthy obesity (MUO) or T2D. Vasodilator function was assessed by infusion of ACh and sodium nitroprusside (SNP). Circulating levels of OPN were higher in the MUO/T2D group than in lean subjects (P < 0.05); OPG and RANTES were higher in MUO/T2D group than in the other groups (both P < 0.001); fetuin-A was not different between groups (P > 0.05); vasodilator responses to either ACh or SNP were impaired in both MUO/T2D and MHO compared with lean subjects (all P < 0.001). In patients with T2D who were enrolled in the intervention trial, antidiabetic treatment with glyburide, metformin, or pioglitazone resulted in a significant reduction of circulating OPG (P = 0.001), without changes in the other biomarkers and vasodilator responses (all P > 0.05). In conclusion, obese patients with MUO/T2D have elevated circulating OPN, OPG, and RANTES; in these patients, antidiabetic treatment reduces only circulating OPG. Further study is needed to better understand the mechanisms of vascular calcifications in obesity and diabetes.

Metabolic profiling of visceral adipose tissue from obese subjects with or without metabolic syndrome.

Obesity represents one of the most complex public health challenges and has recently reached epidemic proportions. Obesity is also considered to be primarily responsible for the rising prevalence of metabolic syndrome, defined as the coexistence in the same individual of several risk factors for atherosclerosis, including dyslipidemia, hypertension and hyperglycemia, as well as for cancer. Additionally, the presence of three of the five risk factors (abdominal obesity, low high-density lipoprotein cholesterol, high triglycerides, high fasting glucose and high blood pressure) characterizes metabolic syndrome, which has serious clinical consequences. The current study was conducted in order to identify metabolic differences in visceral adipose tissue (VAT) collected from obese (body mass index 43-48) human subjects who were diagnosed with metabolic syndrome, obese individuals who were metabolically healthy and nonobese healthy controls. Extensive gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS/MS) analyses were used to obtain the untargeted VAT metabolomic profiles of 481 metabolites belonging to all biochemical pathways. Our results indicated consistent increases in oxidative stress markers from the pathologically obese samples in addition to subtle markers of elevated glucose levels that may be consistent with metabolic syndrome. In the tissue derived from the pathologically obese subjects, there were significantly elevated levels of plasmalogens, which may be increased in response to oxidative changes in addition to changes in glycerolphosphorylcholine, glycerolphosphorylethanolamine glycerolphosphorylserine, ceramides and sphingolipids. These data could be potentially helpful for recognizing new pathways that underlie the metabolic-vascular complications of obesity and may lead to the development of innovative targeted therapies.

Endothelial and Perivascular Adipose Tissue Abnormalities in Obesity-Related Vascular Dysfunction: Novel Targets for Treatment.

The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. In addition to its well-established role in maintaining vascular homeostasis, the endothelium has been increasingly recognized as a key player in modulating healthy adipose tissue expansion in response to excess calories by providing adipocyte precursors and driving angiogenesis. When this increased storage need is unmet, excessive deposition of fat occurs at ectopic locations, including perivascular adipose tissue (PVAT). PVAT is in intimate contact with the vessel wall, hence affecting vascular function and structure. In lean individuals, PVAT exerts anticontractile and anti-inflammatory activities to protect the vasculature. In obesity, instead, these beneficial properties are lost and PVAT releases inflammatory mediators, promotes oxidative stress, and contributes to vascular dysfunction. The underlying mechanisms elicited by these outside-in signals include resistance to the vasodilator actions of insulin and activation of endothelin (ET)-1-mediated vasoconstriction. A number of adipokines and gut hormones, which are important modulators of food intake, energy balance, glucose and lipid metabolism, insulin sensitivity, and inflammation, have also positive vascular actions. This feature makes them promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant benefits. There is, therefore, real hope that unleashing the power of fat- and gut-derived substances might provide effective dual-action therapies for obesity and its complications.

Vasodilator responses and endothelin-dependent vasoconstriction in metabolically healthy obesity and the metabolic syndrome.

Patients with metabolically healthy obesity (MHO) do not present the cluster of metabolic abnormalities that define the metabolic syndrome (MetS). Whether MHO is associated with lower impairment of vasoreactivity than the MetS is unknown. For this purpose, forearm blood flow (FBF) responses were measured by strain-gauge plethysmography during the intra-arterial infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and/or the selective endothelin type A (ETA) receptor blocker BQ-123 in 119 obese individuals with MHO (n = 34) or with the MetS (n = 85) and in healthy lean controls (n = 56). ACh and SNP caused a significant vasodilation in both obese and lean participants (all P < 0.001). However, the response to both agents was significantly lower in the obese than in the control group (both P < 0.001). Among the obese participants, the reactivity to ACh was higher in MHO than in MetS patients, whereas the responsiveness to SNP was equally impaired in both groups (P = 0.45). Infusion of BQ-123 significantly increased FBF in obese patients (P < 0001), but not in the lean participants; hence, FBF following ETA receptor blockade was higher in both obese groups than in controls (both P < 0.001). FBF response to BQ-123 was significantly higher in patients with the MetS than in those with MHO (P = 0.007). In conclusion, patients with MHO have abnormal vascular reactivity, although their endothelial dysfunction is less pronounced than in patients with the MetS. These findings indicate that obesity is associated with vascular damage independent of those metabolic abnormalities underlying the MetS.

Role of L-type Ca2+-channels in the vasorelaxing response to finerenone in arteries of human visceral adipose tissue.

Inadequate blood supply to the expanding adipose tissue (AT) is involved in the unhealthy AT remodeling and cardiometabolic consequences of obesity. Because of the pathophysiological role of upregulated mineralocorticoid receptor (MR) signaling in the complications of obesity, this study tested the vasoactive properties of finerenone, a nonsteroidal MR antagonist, in arteries of human AT. Arteries isolated from the visceral AT of obese subjects were studied in a wire myograph. Finerenone resulted in a concentration-dependent relaxation of arteries precontracted with either the thromboxane-A2 analog U46619, ET-1, or high-K+ solution; the steroidal MR antagonist potassium canrenoate, by contrast, did not relax arteries contracted with either U46619 or high-K+ solution. Finerenone-induced relaxation after precontraction with U46619 was greater in the arteries of obese versus nonobese subjects. Mechanistically, the vasorelaxing response to finerenone was not influenced by preincubation with the nitric oxide synthase inhibitor L-NAME or by endothelium removal. Interestingly, finerenone, like the dihydropyridine Ca2+-channel blocker nifedipine, relaxed arteries contracted with the L-type Ca2+-channel agonist Bay K8644. In conclusion, finerenone relaxes arteries of human visceral AT, likely through antagonism of L-type Ca2+ channels. This finding identifies a novel mechanism by which finerenone may improve AT perfusion, hence protecting against the cardiometabolic complications of obesity.

Oxidative stress in diabetes: implications for vascular and other complications.

In recent decades, oxidative stress has become a focus of interest in most biomedical disciplines and many types of clinical research. Increasing evidence shows that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart failure. Based on these studies, an emerging concept is that oxidative stress is the "final common pathway" through which the risk factors for several diseases exert their deleterious effects. Oxidative stress causes a complex dysregulation of cell metabolism and cell-cell homeostasis; in particular, oxidative stress plays a key role in the pathogenesis of insulin resistance and ß-cell dysfunction. These are the two most relevant mechanisms in the pathophysiology of type 2 diabetes and its vascular complications, the leading cause of death in diabetic patients.

The Role of Perivascular Adipose Tissue in the Pathogenesis of Endothelial Dysfunction in Cardiovascular Diseases and Type 2 Diabetes Mellitus.

Cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) are two of the four major chronic non-communicable diseases (NCDs) representing the leading cause of death worldwide. Several studies demonstrate that endothelial dysfunction (ED) plays a central role in the pathogenesis of these chronic diseases. Although it is well known that systemic chronic inflammation and oxidative stress are primarily involved in the development of ED, recent studies have shown that perivascular adipose tissue (PVAT) is implicated in its pathogenesis, also contributing to the progression of atherosclerosis and to insulin resistance (IR). In this review, we describe the relationship between PVAT and ED, and we also analyse the role of PVAT in the pathogenesis of CVDs and T2DM, further assessing its potential therapeutic target with the aim of restoring normal ED and reducing global cardiovascular risk.

Rho-kinase inhibition improves vasodilator responsiveness during hyperinsulinemia in the metabolic syndrome.

In patients with the metabolic syndrome (MetS), the facilitatory effect of insulin on forearm vasodilator responsiveness to different stimuli is impaired. Whether the RhoA/Rho kinase (ROCK) pathway is involved in this abnormality is unknown. We tested the hypotheses that, in MetS patients, ROCK inhibition with fasudil restores insulin-stimulated vasodilator reactivity and that oxidative stress plays a role in this mechanism. Endothelium-dependent and -independent forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were assessed in MetS patients (n = 8) and healthy controls (n = 5) before and after the addition of fasudil (200 µg/min) to an intra-arterial infusion of insulin (0.1 mU/kg/min). In MetS patients (n = 5), fasudil was also infused without hyperinsulinemia. The possible involvement of oxidative stress in the effect of fasudil during hyperinsulinemia was investigated in MetS patients (n = 5) by infusing vitamin C (25 mg/min). In MetS patients, compared with saline, fasudil enhanced endothelium-dependent and -independent vasodilator responses during insulin infusion (P < 0.001 and P = 0.008, respectively), but not in the absence of hyperinsulinemia (P = 0.25 and P = 0.13, respectively). By contrast, fasudil did not affect vasoreactivity to ACh and SNP during hyperinsulinemia in controls (P = 0.11 and P = 0.56, respectively). In MetS patients, fasudil added to insulin and vitamin C did not further enhance vasodilation to ACh and SNP (P = 0.15 and P = 0.43, respectively). In the forearm circulation of patients with the MetS, ROCK inhibition by fasudil improves endothelium-dependent and -independent vasodilator responsiveness during hyperinsulinemia; increased oxidative stress seems to be involved in the pathophysiology of this phenomenon.

Mirabegron relaxes arteries from human visceral adipose tissue through antagonism of α1-adrenergic receptors.

AIM: As inadequate perfusion has emerged as a key determinant of adipose tissue dysfunction in obesity, interest has grown regarding possible pharmacological interventions to prevent this process. Mirabegron has proved to improve insulin sensitivity and glucose homeostasis in obese humans via stimulation of ß3-adrenoceptors which also seem to mediate endothelium-dependent vasodilation in disparate human vascular beds. We characterized, therefore, the vasomotor function of mirabegron in human adipose tissue arteries and the underlying mechanisms. METHODS: Small arteries (116-734 µm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. After vessels had been contracted, changes in vascular tone in response to mirabegron were determined under different conditions. RESULTS: Mirabegron did not elicit vasorelaxation in vessels contracted with U46619 or high-K+ (both P > 0.05). Notably, mirabegron markedly blunted the contractile effect of the α1-adrenergic receptor agonist phenylephrine (P < 0.001) either in presence or absence of the vascular endothelium. The anti-contractile action of mirabegron on phenylephrine-induced vasoconstriction was not influenced by the presence of the selective ß3-adrenoceptor blocker L-748,337 (P < 0.05); lack of involvement of ß3-adrenoceptors was further supported by absent vascular staining for them at immunohistochemistry. CONCLUSIONS: Mirabegron induces endothelium-independent vasorelaxation in arteries from visceral adipose tissue, likely through antagonism of α1-adrenoceptors.

Variable Changes of Circulating ANGPTL3 and ANGPTL4 in Different Obese Phenotypes: Relationship with Vasodilator Dysfunction.

Obesity associates with premature atherosclerosis and an increased burden of cardiovascular disease, especially when accompanied by abnormalities of lipid and glucose metabolism. Angiopoietin-like (ANGPTL)3 and ANGPTL4 are metabolic regulators, whose upregulation is associated with dyslipidemia, insulin resistance and atherosclerosis. We analyzed, therefore, changes in circulating ANGPTL3 and ANGPTL4 in obese patients with different metabolic phenotypes and their relation with impaired vasodilator reactivity, an early abnormality in atherosclerosis. Compared to the lean subjects (n = 42), circulating ANGPTL3 was elevated (both p > 0.001) in the patients with metabolically unhealthy obesity (MUO; n = 87) and type 2 diabetes (T2D; n = 31), but not in those with metabolically healthy obesity (MHO; n = 48, p > 0.05). Circulating ANGPTL4, by contrast, was increased in all obese subgroups (all p < 0.001 vs. lean subjects). Vasodilator responses to both acetylcholine and sodium nitroprusside were reduced in the three obese subgroups vs. lean subjects (all p < 0.001), with greater impairment in the patients with T2D than in those with MHO and MUO (all p < 0.05). In the whole population, an inverse relationship (r = 0.27; p = 0.003) was observed between circulating ANGPTL4 and endothelium-dependent vasorelaxation. Circulating ANGPTL3 and ANGPTL4 undergo variable changes in obese patients with different metabolic phenotypes; changes in ANGPTL4 relate to endothelial dysfunction, making this protein a possible target for vascular prevention in these patients.

Mechanisms of SGLT2 (Sodium-Glucose Transporter Type 2) Inhibition-Induced Relaxation in Arteries From Human Visceral Adipose Tissue.

As novel drug treatments for diabetes have shown favorable cardiovascular effects, interest has mounted with regard to their possible vascular actions, particularly in relation to visceral adipose tissue perfusion and remodeling in obesity. The present study tested the vasorelaxing effect of the SGLT2 (sodium-glucose transporter type 2) inhibitor canagliflozin in arteries from visceral adipose tissue of either nonobese or obese humans and investigated the underlying mechanisms. Also, the vasorelaxing effect of canagliflozin and the GLP-1 (glucagon-like peptide 1) agonist liraglutide were compared in arteries from obese patients. To these purposes, small arteries (116-734 µm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. Canagliflozin elicited a higher concentration-dependent vasorelaxation in arterioles from obese than nonobese individuals (P=0.02). The vasorelaxing response to canagliflozin was not modified (P=0.93) by inhibition of nitric oxide synthase (L-NAME) or prostacyclin (indomethacin), or by H2O2 scavenging (catalase); also, canagliflozin-induced relaxation was similar (P=0.23) in endothelium-intact or -denuded arteries precontracted with high potassium concentration, thereby excluding an involvement of endothelium-derived hyperpolarizing factors. The vasorelaxing response to canagliflozin was similar to that elicited by the Na+/H+ exchanger 1 inhibitor BIX (P=0.67), but greater than that to the Na+/Ca++ exchanger inhibitor SEA 0400 (P=0.001), hinting a role of Na+/H+ exchanger inhibition in canagliflozin-induced relaxation. In arterioles from obese patients, the vasorelaxing response to canagliflozin was greater than that to liraglutide (P=0.004). These findings demonstrate that canagliflozin induces endothelium-independent vasorelaxation in arterioles from human visceral adipose tissue, thereby suggesting that SGLT2 inhibition might favorably impact the processes linking visceral adipose burden to vascular disease in obesity.

Gut Dysbiosis and Western Diet in the Pathogenesis of Essential Arterial Hypertension: A Narrative Review.

Metabolic syndrome is a cluster of the most dangerous cardiovascular (CV) risk factors including visceral obesity, insulin resistance, hyperglycemia, alterations in lipid metabolism and arterial hypertension (AH). In particular, AH plays a key role in the complications associated with metabolic syndrome. High salt intake is a well-known risk factor for AH and CV diseases. Vasoconstriction, impaired vasodilation, extracellular volume expansion, inflammation, and an increased sympathetic nervous system (SNS) activity are the mechanisms involved in the pathogenesis of AH, induced by Western diet. Gut dysbiosis in AH is associated with reduction of short chain fatty acid-producing bacteria: acetate, butyrate and propionate, which activate different pathways, causing vasoconstriction, impaired vasodilation, salt and water retention and a consequent high blood pressure. Moreover, increased trimethylamine N-oxide and lipopolysaccharides trigger chronic inflammation, which contributes to endothelial dysfunction and target organs damage. Additionally, a high salt-intake diet impacts negatively on gut microbiota composition. A bidirectional neuronal pathway determines the "brain-gut" axis, which, in turn, influences blood pressure levels. Then, we discuss the possible adjuvant novel treatments related to gut microbiota modulation for AH control.

Association of Gut Hormones and Microbiota with Vascular Dysfunction in Obesity.

In the past few decades, obesity has reached pandemic proportions. Obesity is among the main risk factors for cardiovascular diseases, since chronic fat accumulation leads to dysfunction in vascular endothelium and to a precocious arterial stiffness. So far, not all the mechanisms linking adipose tissue and vascular reactivity have been explained. Recently, novel findings reported interesting pathological link between endothelial dysfunction with gut hormones and gut microbiota and energy homeostasis. These findings suggest an active role of gut secretome in regulating the mediators of vascular function, such as nitric oxide (NO) and endothelin-1 (ET-1) that need to be further investigated. Moreover, a central role of brain has been suggested as a main player in the regulation of the different factors and hormones beyond these complex mechanisms. The aim of the present review is to discuss the state of the art in this field, by focusing on the processes leading to endothelial dysfunction mediated by obesity and metabolic diseases, such as insulin resistance. The role of perivascular adipose tissue (PVAT), gut hormones, gut microbiota dysbiosis, and the CNS function in controlling satiety have been considered. Further understanding the crosstalk between these complex mechanisms will allow us to better design novel strategies for the prevention of obesity and its complications.