Endothelin-1 down-regulates nuclear factor erythroid 2-related factor-2 and contributes to perivascular adipose tissue dysfunction in obesity.

Perivascular adipose tissue (PVAT) negatively regulates vascular muscle contraction. However, in the context of obesity, the PVAT releases vasoconstrictor substances that detrimentally affect vascular function. A pivotal player in this scenario is the peptide endothelin-1 (ET-1), which induces oxidative stress and disrupts vascular function. The present study postulates that obesity augments ET-1 production in the PVAT, decreases the function of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, further increasing reactive oxygen species (ROS) generation, culminating in PVAT dysfunction. Male C57BL/6 mice were fed either a standard or a high-fat diet for 16 weeks. Mice were also treated with saline or a daily dose of 100 mg·kg-1 of the ETA and ETB receptor antagonist Bosentan, for 7 days. Vascular function was evaluated in thoracic aortic rings, with and without PVAT. Mechanistic studies utilized PVAT from all groups and cultured WT-1 mouse brown adipocytes. PVAT from obese mice exhibited increased ET-1 production, increased ECE1 and ETA gene expression, loss of the anticontractile effect, as well as increased ROS production, decreased Nrf2 activity, and downregulated expression of Nrf2-targeted antioxidant genes. PVAT of obese mice also exhibited increased expression of Tyr216-phosphorylated-GSK3ß and KEAP1, but not BACH1 - negative Nrf2 regulators. Bosentan treatment reversed all these effects. Similarly, ET-1 increased ROS generation and decreased Nrf2 activity in brown adipocytes, events mitigated by BQ123 (ETA receptor antagonist). These findings place ET-1 as a major contributor to PVAT dysfunction in obesity and highlight that pharmacological control of ET-1 effects restores PVAT's cardiovascular protective role.

Sex-Specific Effects of Cholesteryl Ester Transfer Protein (CETP) on the Perivascular Adipose Tissue.

Cholesteryl ester transfer protein (CETP) increases the atherosclerosis risk by lowering HDL-cholesterol levels. It also exhibits tissue-specific effects independent of HDL. However, sexual dimorphism of CETP effects remains largely unexplored. Here, we hypothesized that CETP impacts the perivascular adipose tissue (PVAT) phenotype and function in a sex-specific manner. PVAT function, gene and protein expression, and morphology were examined in male and female transgenic mice expressing human or simian CETP and their non-transgenic counterparts (NTg). PVAT exerted its anticontractile effect in aortas from NTg males, NTg females, and CETP females, but not in CETP males. CETP male PVAT had reduced NO levels, decreased eNOS and phospho-eNOS levels, oxidative stress, increased NOX1 and 2, and decreased SOD2 and 3 expressions. In contrast, CETP-expressing female PVAT displayed increased NO and phospho-eNOS levels with unchanged NOX expression. NOX inhibition and the antioxidant tempol restored PVAT anticontractile function in CETP males. Ex vivo estrogen treatment also restored PVAT function in CETP males. Moreover, CETP males, but not female PVAT, show increased inflammatory markers. PVAT lipid content increased in CETP males but decreased in CETP females, while PVAT cholesterol content increased in CETP females. CETP male PVAT exhibited elevated leptin and reduced Prdm16 (brown adipocyte marker) expression. These findings highlight CETP sex-specific impact on PVAT. In males, CETP impaired PVAT anticontractile function, accompanied by oxidative stress, inflammation, and whitening. Conversely, in females, CETP expression increased NO levels, induced an anti-inflammatory phenotype, and preserved the anticontractile function. This study reveals sex-specific vascular dysfunction mediated by CETP.

ß-Adrenergic Stimulation-Induced PVAT Dysfunction in Male Sex: A Role for 11ß-Hydroxysteroid Dehydrogenase-1.

Long-term ß-adrenoceptor (ß-AR) stimulation is a pathological mechanism associated with cardiovascular diseases resulting in endothelial and perivascular adipose tissue (PVAT) dysfunction. In this study, we aimed to identify whether ß-adrenergic signaling has a direct effect on PVAT. Thoracic aorta PVAT was obtained from male Wistar rats and cultured ex vivo with the ß-AR agonist isoproterenol (Iso; 1 µM) or vehicle for 24 hours. Conditioned culture medium (CCM) from Iso-treated PVAT induced a marked increase in aorta contractile response, induced oxidative stress, and reduced nitric oxide production in PVAT compared to vehicle. In addition, Iso-treated PVAT and PVAT-derived differentiated adipocytes exhibited higher corticosterone release and protein expression of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an enzyme responsible for de novo synthesis of corticosterone. Macrophages exposed to Iso also exhibited increased corticosterone release in response to ß-AR stimulation. Incubation of Iso-treated PVAT and PVAT-derived differentiated adipocytes with ß3-AR antagonist restored aorta contractile function modulated by Iso-CCM and normalized 11ß-HSD1 protein expression. These results show that ß3-AR signaling leads to upregulation of 11ß-HSD1 in PVAT, thus increasing corticosterone release and contributing to impair the anticontractile function of this tissue.

Vasodilator Responses of Perivascular Adipose Tissue-Derived Hydrogen Sulfide Stimulated with L-Cysteine in Pregnancy Hypertension-Induced Endothelial Dysfunction in Rats.

Endothelium-derived nitric oxide (NO)-induced vasodilation is impaired in pregnancy hypertension. However, the role of perivascular adipose tissue (PVAT)-derived hydrogen sulfide (H2S), as an alternative for counteracting vascular dysfunction, is incompletely clear in hypertensive disorders of pregnancy. Therefore, PVAT-derived H2S-induced vasodilation was investigated in pregnancy hypertension-induced endothelial dysfunction. Non-pregnant (Non-Preg) and pregnant (Preg) rats were submitted (or not) to the deoxycorticosterone (DOCA)-salt protocol and assigned as follows (n = 10/group): Non-Preg, Non-Preg+DOCA, Preg, and Preg+DOCA groups. Systolic blood pressure (SBP), angiogenesis-related factors, determinant levels of H2S (PbS), NO (NOx), and oxidative stress (MDA) were assessed. Vascular changes were recorded in thoracic aortas with PVAT and endothelium (intact and removed layers). Vasorelaxation responses to the substrate (L-cysteine) for the H2S-producing enzyme cystathionine-γ-lyase (CSE) were examined in the absence and presence of CSE-inhibitor DL-propargylglycine (PAG) in thoracic aorta rings pre-incubated with cofactor for CSE (pyridoxal-5 phosphate: PLP) and pre-contracted with phenylephrine. Hypertension was only found in the Preg+DOCA group. Preg+DOCA rats showed angiogenic imbalances and increased levels of MDA. PbS, but not NOx, showed increased levels in the Preg+DOCA group. Pre-incubation with PLP and L-cysteine elevated determinants of H2S in PVAT and placentas of Preg-DOCA rats, whereas no changes were found in the aortas without PVAT. Aortas of Preg-DOCA rats showed that PVAT-derived H2S-dependent vasodilation was greater compared to endothelium-derived H2S, whereas PAG blocked these responses. PVAT-derived H2S endogenously stimulated with the amino acid L-cysteine may be an alternative to induce vasorelaxation in endothelial dysfunction related to pregnancy hypertension.

AT1 receptors modulate ethanol-induced loss of anticontractile effect of perivascular adipose tissue.

Ethanol consumption activates renin-angiotensin-aldosterone system (RAAS), which plays a major role in the pro-contractile and hypertensive effects linked to ethanol. We hypothesized that ethanol consumption induces loss of the anticontractile effect of perivascular adipose tissue (PVAT)through RAAS-mediated mechanisms. We examined the contribution of angiotensin II type 1 receptors (AT1R) to ethanol-induced PVAT dysfunction. With this purpose, male Wistar Hannover rats were treated with ethanol 20 % (in volume ratio) and/or losartan (antagonist of AT1R; 10 mg/kg/day, gavage) for 9 weeks. Losartan prevented the increase in blood pressure and the loss of the anticontractile effect of PVAT induced by ethanol consumption. PVAT dysfunction occurred after 3 and 9 weeks of treatment with ethanol in an endothelium-dependent manner. Blockade of AT1R prevented ethanol-induced reduction of adiponectin levels in PVAT from ethanol-treated rats. Functional assays revealed that ethanol impaired the anticontractile effect of PVAT-derived angiotensin (1-7) and endothelial nitric oxide (NO). In conclusion, AT1R are implicated in ethanol-induced loss of the anticontractile effect of PVAT. In PVAT, AT1R activation decreases the production of adiponectin, a PVAT-derived factor that promotes vasorelaxation in an endothelium-dependent manner. In the endothelium, AT1R favors the production of superoxide (O2•-) leading to a reduction in NO bioavailability. These responses impair the vasodilator action induced by PVAT-derived angiotensin (1-7), which occurs via Mas receptors located in endothelial cells. Ethanol-induced PVAT dysfunction favors vascular hypercontractility, a response that could contribute to the hypertensive state associated with ethanol consumption.

Insights by which TUDCA is a potential therapy against adiposity.

Adipose tissue is an organ with metabolic and endocrine activity. White, brown and ectopic adipose tissues have different structure, location, and function. Adipose tissue regulates energy homeostasis, providing energy in nutrient-deficient conditions and storing it in high-supply conditions. To attend to the high demand for energy storage during obesity, the adipose tissue undergoes morphological, functional and molecular changes. Endoplasmic reticulum (ER) stress has been evidenced as a molecular hallmark of metabolic disorders. In this sense, the ER stress inhibitor tauroursodeoxycholic acid (TUDCA), a bile acid conjugated to taurine with chemical chaperone activity, has emerged as a therapeutic strategy to minimize adipose tissue dysfunction and metabolic alterations associated with obesity. In this review, we highlight the effects of TUDCA and receptors TGR5 and FXR on adipose tissue in the setting of obesity. TUDCA has been demonstrated to limit metabolic disturbs associated to obesity by inhibiting ER stress, inflammation, and apoptosis in adipocytes. The beneficial effect of TUDCA on perivascular adipose tissue (PVAT) function and adiponectin release may be related to cardiovascular protection in obesity, although more studies are needed to clarify the mechanisms. Therefore, TUDCA has emerged as a potential therapeutic strategy for obesity and comorbidities.

Ethanol consumption favors pro-contractile phenotype of perivascular adipose tissue: A role for interleukin-6.

Perivascular adipose tissue (PVAT) exerts anticontractile effect, but under non-physiological conditions it may contribute to vascular dysfunction by releasing pro-inflammatory cytokines. Since PVAT is an important source of interleukin (IL)-6, we evaluated whether this cytokine would contribute to ethanol-induced vascular dysfunction. With this purpose, male C57BL/6 wild-type (WT) or IL-6-deficient mice (IL-6-/-) were treated with ethanol for 12 weeks. Increased blood pressure was evidenced after 4 and 6 weeks of treatment with ethanol in WT and IL-6-/- mice, respectively. In WT mice, ethanol increased plasma and PVAT levels of IL-6. Ethanol favoured pro-contractile phenotype of PVAT in mesenteric arteries from WT, but not IL-6-deficient mice. Functional studies showed that tiron [(a scavenger of superoxide (O2-)] reversed the pro-contractile effect of PVAT in mesenteric arteries from ethanol-treated mice. Ethanol increased the levels of O2- in PVAT from WT mice. Ethanol-induced increase in O2- generation was higher in arteries with PVAT from WT mice when compared to IL-6-deficient mice. Treatment with ethanol augmented myeloperoxidase activity in the mesenteric arterial bed (MAB; with or without PVAT) from WT, but not IL-6-deficient mice. In conclusion, IL-6 contributes to the pro-contractile effect of PVAT by a mechanism that involves increase in ROS generation. Additionally, IL-6 mediates intravascular recruitment of neutrophils in response to ethanol and plays a role in the early stages of ethanol-induced hypertension. Collectively, our findings provide novel evidence for a role of IL-6 in the vascular dysfunction induced by ethanol.

miRNA-22 is involved in the aortic reactivity in physiological conditions and mediates obesity-induced perivascular adipose tissue dysfunction.

AIMS: Blood vessels are surrounded by perivascular adipose tissue (PVAT), which plays an important role in vascular tonus regulation due to its anticontractile effect; however, this effect is impaired in obesity. We previously demonstrated that miRNA-22 is involved in obesity-related metabolic disorders. However, the impact of miRNA-22 on vascular reactivity and PVAT function is unknown. AIM: To investigate the role of miRNA-22 on vascular reactivity and its impact on obesity-induced PVAT dysfunction. MAIN METHODS: Wild-type and miRNA-22 knockout (KO) mice were fed a control or a high-fat (HF) diet. To characterize the vascular response, concentration-responses curves to noradrenaline were performed in PVAT- or PVAT+ thoracic aortic rings in absence and presence of L-NAME. Expression of adipogenic and thermogenic markers and NOS isoforms were evaluated by western blotting or qPCR. KEY FINDINGS: HF diet and miRNA-22 deletion reduced noradrenaline-induced contraction in PVAT- aortic rings. Additionally, miRNA-22 deletion increased noradrenaline-induced contraction in PVAT+ aortic rings without affecting its sensitivity; however, this effect was not observed in miRNA-22 KO mice fed a HF diet. Interestingly, miRNA-22 deletion reduced the contraction of aortic rings to noradrenaline via a NOS-dependent mechanism. Moreover, HF diet abolished the NOS-mediated anticontractile effect of PVAT, which was attenuated by miRNA-22 deletion. Mechanistically, we found that PVAT from miRNA-22 KO mice fed a HF diet presented increased protein expression of nNOS. SIGNIFICANCE: These results suggest that miRNA-22 is important for aorta reactivity under physiological circumstances and its deletion attenuates the loss of the NOS-mediated anticontractile effect of PVAT in obesity.

Effects of High-Fat and High-Fat/High-Sucrose Diet-Induced Obesity on PVAT Modulation of Vascular Function in Male and Female Mice.

Increased adiposity in perivascular adipose tissue (PVAT) has been related to vascular dysfunction. High-fat (HF) diet-induced obesity models are often used to analyze the translational impact of obesity, but differences in sex and Western diet type complicate comparisons between studies. The role of PVAT was investigated in small mesenteric arteries (SMAs) of male and female mice fed a HF or a HF plus high-sucrose (HF + HS) diet for 3 or 5 months and compared them to age/sex-matched mice fed a chow diet. Vascular responses of SMAs without (PVAT-) or with PVAT (PVAT+) were evaluated. HF and HF + HS diets increased body weight, adiposity, and fasting glucose and insulin levels without affecting blood pressure and circulating adiponectin levels in both sexes. HF or HF + HS diet impaired PVAT anticontractile effects in SMAs from females but not males. PVAT-mediated endothelial dysfunction in SMAs from female mice after 3 months of a HF + HS diet, whereas in males, this effect was observed only after 5 months of HF + HS diet. However, PVAT did not impact acetylcholine-induced relaxation in SMAs from both sexes fed HF diet. The findings suggest that the addition of sucrose to a HF diet accelerates PVAT dysfunction in both sexes. PVAT dysfunction in response to both diets was observed early in females compared to age-matched males suggesting a susceptibility of the female sex to PVAT-mediated vascular complications in the setting of obesity. The data illustrate the importance of the duration and composition of obesogenic diets for investigating sex-specific treatments and pharmacological targets for obesity-induced vascular complications.

Perivascular adipose tissue and microvascular endothelial dysfunction in obese mice: Beneficial effects of aerobic exercise in adiponectin receptor (AdipoR1) and peNOSSer1177.

In the present study, we aim to investigate the effects of aerobic physical training on perivascular adipose tissue (PVAT)-induced microvascular dysfunction of the femoral artery in obese mice. Microvascular reactivity was evaluated in control sedentary (c-SD), obese sedentary (o-SD) and obese trained (o-TR) male mice (C57BL6/JUnib), in the absence (PVAT-) or the presence (PVAT+) of femoral artery PVAT. We also analyzed protein expression, vascular nitric oxide (NO) production and reactive oxygen species (ROS) generation in PVAT. The blood glucose, triglycerides and total cholesterol levels were increased in the o-SD group, when compared with the c-SD group. The maximal responses and the potency to acetylcholine (ACh) were decreased in PVAT+ compared with PVAT- rings in the o-SD group, accompanied by a decrease in vascular protein expression of peNOSSer1177 , Cu/Zn-SOD, leptin receptor (Ob-R) and adiponectin receptor (AdipoR1). The protein expression of leptin increased and that of adiponectin decreased in PVAT. Additionally, vascular NO production was reduced and ROS generation was enhanced in PVAT in the o-SD group. Aerobic exercise training was effective for normalizing ACh relaxation response, vascular NO production and ROS generation in the o-TR group. It partially re-established the vascular protein expression of peNOSSer1177 and the PVAT leptin; normalized the vascular Cu/Zn-SOD and AdipoR1 protein expressions. In obese sedentary mice, the presence of PVAT is involved in the process of microvascular dysfunction of the femoral artery in a pathway associated with increased inflammation and ROS generation. The aerobic exercise training normalized the vascular response, the NO production and/or bioavailability and oxidative stress, with improved vascular expressions of Cu/Zn-SOD, peNOSser1177 , and AdipoR1.

NO, ROS, RAS, and PVAT: More Than a Soup of Letters.

Perivascular adipose tissue (PVAT) has recently entered in the realm of cardiovascular diseases as a putative target for intervention. Notwithstanding its relevance, there is still a long way before the role of PVAT in physiology and pathology is fully understood. The general idea that PVAT anti-contractile effect is beneficial and its pro-contractile effect is harmful is being questioned by several reports. The role of some PVAT important products or systems such as nitric oxide (NO), reactive oxygen species (ROS), and RAS may vary depending on the context, disease, place of production, etc., which adds doubts on how mediators of PVAT anti- and pro-contractile effects are called to action and their final result. This short review will address some points regarding NO, ROS, and RAS in the beneficial and harmful roles of PVAT.

Microscopic analysis of the myocardial bridges and their relationship with atheromatous plaque / Análisis microscópico de los puentes miocárdicos y su relación con la placa ateromatosa

SUMMARY: Most histopathological studies have reported that the segment of the coronary artery below the myocardial bridge does not present atheromatous plaque, while the segment proximal to the myocardial bridge may have it. The aim of this study was to evaluate the microscopic environment of myocardial bridges. This descriptive study was carried out with 60 hearts of individuals who underwent autopsy at the National Institute of Legal Medicine and Forensic Sciences in Bucaramanga-Colombia. For each specimen, the coronary arteries and their branches were dissected, removing the subepicardial adipose tissue to identify the myocardial bridges and obtain histological sections of the compromised arterial branches. The presence of myocardial bridges was observed in 22 hearts (36.7%) with a length of 17.31 + 4.41 mm and a thickness of 904.57 + 312.27 mm. The coronary vessel caliber at the prepontine level was 246.57 + 49.33 mm and was significantly higher than in the pontine (188.92 + 60.55 mm) and postpontin (190.40 + 47 mm) segments (p=0.001 for both values). Atheromatous plaque was observed in the prepontine segment in 12 cases (46.15 %) and in 8 samples (30.76%) at the pontine level, but in this segment, there was slight damage to the vascular endothelium, or phase I level. The thickness of the tunica intima in the cases with atheromatous plaque was 15.68 + 13.39 mm and that of the plaque-free segments was 5.10 + 4.40 mm (p=0.005), and in the pontine segment the overlying periarterial adipose tissue had a thickness of 72.01 + 69.44 mm, which was higher than the other three locations (p=0.005). The morphometry of the perivascular fat pad and the presence of phase I atheromatous plaque are the main contributions of this study to the histology of myocardial bridges.

RESUMEN: La mayoría de los estudios histopatológicos han reportado que el segmento de la arteria coronaria debajo del puente miocárdico no presenta placa ateromatosa, mientras que el segmento proximal al puente miocárdico puede tenerla. El objetivo de este estudio fue evaluar el entorno microscópico de los puentes miocárdico. Este estudio descriptivo se realizó con 60 corazones de individuos a quienes se les práctico autopsia en el Instituto Nacional de Medicina Legal y Ciencias Forenses de Bucaramanga-Colombia. Para cada espécimen se realizó disección de las arterias coronarias y sus ramas, eliminando el tejido adiposo subepicárdico para identificar los puentes miocárdicos y obtener secciones histológicas de las ramas arteriales comprometidas. Se observó presencia de puentes miocárdicos en 22 corazones (36,7 %) con una longitud de 17.31 + 4.41 mm y un espesor de 904.57 + 312.27 mm. El calibre del vaso coronario a nivel prepontino fue 246.57 + 49.33 mm y fue significativamente mayor que en el segmento pontino (188.92 + 60.55 mm) y pospontino (190.40 + 47 mm) (p=0.001 para ambos valores). Se observó placa ateromatosa en el segmento prepontino en 12 casos (46.15 %) y en 8 muestras (30.76%) al nivel pontino, pero en este segmento, correspondieron a fase I, con ligero daño en el endotelio vascular. El espesor de la túnica íntima en los casos con placa ateromatosa fue de 15.68 + 13.39 mm y de los segmentos libres de placa fue 5.10 + 4.40 mm (p=0.005) y en el segmento pontino el tejido adiposo periarterial suprayacente presento un espesor de 72.01 + 69.44 mm, el cual fue mayor a las otras tres ubicaciones (p=0.005). La morfometría de la almohadilla adiposa perivascular y la presencia de placa ateromatosa en fase I son los principales aportes de este estudio a la histología de los puentes miocárdicos.

Melatonin reverses the loss of the anticontractile effect of perivascular adipose tissue in obese rats.

Perivascular adipose tissue (PVAT) undergoes functional changes in obesity. Increased oxidative stress is a central mechanism whereby obesity induces loss of the anticontractile effect of PVAT. Melatonin is an antioxidant that displays vasoprotective action in cardiovascular disease. Here, we sought to investigate whether melatonin would restore the anticontractile effect of periaortic PVAT in obesity. Male Wistar Hannover rats were treated for 10 weeks with a high-calorie diet. Melatonin (5 mg/kg/d, p.o., gavage) was administered for 2 weeks. Functional findings showed that obesity-induced loss of the anticontractile effect of PVAT and treatment with melatonin reversed this response. Tiron [a scavenger of superoxide anion (O2 - )] restored the anticontractile effect of PVAT in aortas from obese rats, suggesting a role for reactive oxygen species (ROS) in such response. Decreased superoxide dismutase (SOD) activity and augmented levels of ROS were detected in periaortic PVAT from obese rats. These responses were accompanied by decreased levels of nitric oxide (NO) in PVAT. Treatment with melatonin restored SOD activity, decreased ROS levels, and increased NO bioavailability in PVAT from obese rats. Here, we first reported the beneficial effects of melatonin in periaortic PVAT in obesity. Melatonin reversed the adverse effects of obesity in PVAT that included overproduction of ROS, reduced SOD activity, and decreased bioavailability of NO. Therefore, PVAT may constitute an important target for the treatment of obesity-induced vascular dysfunction and melatonin emerges as a potential tool in the management of the vascular complications induced by obesity.

Renin-angiotensin system overactivation in perivascular adipose tissue contributes to vascular dysfunction in heart failure.

Perivascular adipose tissue (PVAT) dysfunction is associated with vascular damage in cardiometabolic diseases. Although heart failure (HF)-induced endothelial dysfunction is associated with renin-angiotensin system (RAS) activation, no data have correlated this syndrome with PVAT dysfunction. Thus, the aim of the present study was to investigate whether the hyperactivation of the RAS in PVAT participates in the vascular dysfunction observed in rats with HF after myocardial infarction surgery. Wire myograph studies were carried out in thoracic aorta rings in the presence and absence of PVAT. An anticontractile effect of PVAT was observed in the rings of the control rats in the presence (33%) or absence (11%) of endothelium. Moreover, this response was substantially reduced in animals with HF (5%), and acute type 1 angiotensin II receptor (AT1R) and type 2 angiotensin II receptor (AT2R) blockade restored the anticontractile effect of PVAT. In addition, the angiotensin-converting enzyme 1 (ACE1) activity (26%) and angiotensin II levels (51%), as well as the AT1R and AT2R gene expression, were enhanced in the PVAT of rats with HF. Associated with these alterations, HF-induced lower nitric oxide bioavailability, oxidative stress and whitening of the PVAT, which suggests changes in the secretory function of this tissue. The ACE1/angiotensin II/AT1R and AT2R axes are involved in thoracic aorta PVAT dysfunction in rats with HF. These results suggest PVAT as a target in the pathophysiology of vascular dysfunction in HF and provide new perspectives for the treatment of this syndrome.

Modulation of Vascular Function by Perivascular Adipose Tissue: Sex Differences.

In addition to the endothelium, the perivascular adipose tissue (PVAT) has been described to be involved in the local modulation of vascular function by synthetizing and releasing vasoactive factors. Under physiological conditions, PVAT has anticontractile and anti-inflammatory effects. However, in the context of hypertension, obesity and type 2 diabetes, the PVAT pattern of anticontractile adipokines is altered, favoring oxidative stress, inflammation and, consequently, vascular dysfunction. Therefore, dysfunctional PVAT has become a target for therapeutic intervention in cardiometabolic diseases. An increasing number of studies have revealed sex differences in PVAT morphology and in the modulatory effects of PVAT on endothelial function and vascular tone. Moreover, distinct mechanisms underlying PVAT dysfunction may account for vascular abnormalities in males and females. Therefore, targeting sex-specific mechanisms of PVAT dysfunction in cardiovascular diseases is an evolving strategy for cardiovascular protection.

Perivascular adipose tissue phenotype and sepsis vascular dysfunction: Differential contribution of NO, ROS and beta 3-adrenergic receptor.

AIMS: Vascular dysfunction plays a key role in sepsis but the role of perivascular adipose tissue (PVAT) in this condition is relatively unknown. MAIN METHODS: Sepsis was induced by cecal ligation and puncture (CLP). The responses of the aorta and superior mesenteric artery to norepinephrine in the presence or absence of PVAT were evaluated. Fluorescent probes measured the production of nitric oxide (NO) and reactive oxygen species (ROS). NO synthases (NOS) and ß3-adrenoceptor expression were detected by immunofluorescence and S-nitrosylation by the biotin switch assay. KEY FINDINGS: Aorta and superior mesenteric arteries from septic animals with intact PVAT showed a worsened response to the vasoconstrictor compared to vessels without PVAT. PVAT from the aorta (APVAT) produced NO and ROS whereas PVAT from the superior mesenteric artery (MPVAT) produced only ROS. Septic APVAT exhibited a higher density of NOS-1 and NOS-3. S-nitrosylation was found in APVAT. Donor (PVAT obtained from normal or septic rats):Host (normal vessel without PVAT) experiments showed that L-NAME, ODQ and ß3-adrenergic receptor antagonist blocked the septic APVAT anti-contractile effect. None of these compounds affected MPVAT; tempol, but not apocynin, blocked its anti-contractile effect. SIGNIFICANCE: PVAT contributes to the anti-contractile effect in the aorta and mesenteric artery of septic rats through different pathways. ß3-Adrenergic receptor and NO appear to be key mediators of this effect in APVAT, but not in MPVAT where ROS seem to be a relevant mediator. Therefore, PVAT is a relevant player of sepsis vascular dysfunction.

Perivascular Adipose Tissue Oxidative Stress on the Pathophysiology of Cardiometabolic Diseases.

Most of the systemic blood vessels are surrounded by the perivascular adipose tissue (PVAT). Healthy PVAT is anticontractile and anti-inflammatory, but a dysfunctional PVAT has been suggested to link cardiometabolic risk factors to vascular dysfunction. Vascular oxidative stress is an important pathophysiological event in cardiometabolic complications of obesity, type 2 diabetes, and hypertension. PVAT-derived adipocytes generate reactive oxygen species (ROS) including superoxide anion and hydrogen peroxide that might signal to the vascular wall. Therefore, an abnormal generation of ROS by PVAT emerges as a potential pathophysiological mechanism underlying vascular injury. This review summarizes new findings describing ROS production in the PVAT of several vascular beds, major sources of ROS in this tissue including mitochondria, NADPH oxidase and eNOS uncoupled, and finally, changes in ROS production affecting vascular function in the presence of cardiometabolic risk factors and diseases.

Perivascular adipose tissue contributes to lethal sepsis-induced vasoplegia in rats.

It is well established that sepsis induces vascular hyporesponsiveness to vasoconstrictors. Perivascular adipose tissue (PVAT) displays anti-contractile action in various blood vessels. We hypothesized that sepsis would increase the anti-contractile effect of PVAT aggravating sepsis-induced vasoplegia. Male Wistar Hannover rats were subjected to lethal sepsis by cecal ligation and puncture (CLP) method. Aorta or PVAT were collected for functional or biochemical assays 6 h after CLP surgery. Functional experiments showed that sepsis increased the anti-contractile action of PVAT in both endothelium-intact and endothelium-denuded aortas. Carboxy-PTIO, L-NAME and ODQ reversed the hypocontractility mediated by PVAT in aortas from septic rats. Inhibition of nNOS and iNOS with 7-nitroindazole and 1400 W attenuated PVAT-mediated hypocontractility during sepsis. Similar results were found in the presence of indomethacin and Ro1138452, a selective prostacyclin IP receptor antagonist. However, neither tiron nor catalase affected phenylephrine-induced contraction in aortas from septic rats. Increased levels of superoxide anion (O2•-) and 6-keto-prostaglandin F1α (stable product of prostacyclin) were detected in PVAT from septic rats. In situ quantification of reactive oxygen species and nitric oxide (NO) using fluorescent dyes revealed increased levels of both in PVAT from septic rats. The novelty of our study is that PVAT contributes to sepsis-induced vasoplegia by releasing NO and prostacyclin. These findings suggested that signaling pathways in PVAT may be considered as potential novel pharmacological therapeutic targets during sepsis-induced vasoplegia.

Aerobic Exercise Training Prevents Perivascular Adipose Tissue-Induced Endothelial Dysfunction in Thoracic Aorta of Obese Mice.

Background: The mechanisms underlying the perivascular adipose tissue (PVAT) dysfunction in obesity are closely related to inflammation and oxidative stress. The present study aimed to investigate the effects of aerobic exercise training on PVAT-induced endothelial dysfunction of thoracic aorta of obese mice. Methods: Male mice C57BL6/JUnib (6-7 weeks) were divided into: sedentary (c-SD), trained (c-TR), obese sedentary (o-SD), and obese trained (o-TR). Obesity was induced by 16 weeks of high-fat diet and exercise training of moderate intensity started after 8 weeks of protocol and was performed on a treadmill, 5 days/week, for more 8 weeks, 60 min per session. The vascular responsiveness was performed in thoracic aorta in the absence (PVAT-) or in the presence (PVAT+) of PVAT. We analyzed circulatory parameters, protein expression, vascular nitric oxide (NO) production, and reactive oxygen species (ROS) in PVAT. Results: The maximal responses to acetylcholine (ACh) were reduced in PVAT+ compared with PVAT- rings in the o-SD group, accompanied by an increase in circulating glucose, insulin, resistin, leptin, and TNF-α. Additionally, the protein expression of iNOS and generation of ROS were increased in PVAT and production of vascular NO was reduced in the o-SD group compared with c-SD. In the o-TR group, the relaxation response to ACh was completely restored and the circulatory TNF-α, iNOS protein expression, and ROS were normalized with increased expression of Mn-SOD in PVAT, resulting in enhanced vascular NO production. Conclusion: The PVAT-induced endothelial dysfunction in thoracic aorta of obese mice, associated with circulatory inflammation and oxidative stress. Aerobic exercise training upregulated the anti-oxidant expression and decreased PVAT oxidative stress with beneficial impact on endothelium-dependent relaxation.

Hydrogen peroxide and nitric oxide induce anticontractile effect of perivascular adipose tissue via renin angiotensin system activation.

The perivascular adipose tissue (PVAT) is located around the adventitia, composed primarily by adipocytes, stromal cells, leukocytes, fibroblasts and capillaries. It is well described that PVAT is an important modulator of the vascular tone being considered a biologically active tissue, releasing both vasoconstrictor and vasodilators factors. The literature shows that the anti-contractile effect induced by PVAT may be due to activation of the renin-angiotensin system (RAS). AIM: Investigate whether the renin-angiotensin system participates in the effect exerted by perivascular adipose tissue on the vascular tone. METHODS AND RESULTS: For this study we used thoracic aorta from Balb/c mice and performed vascular reactivity, nitric oxide and hydrogen peroxide quantification using selective probes and fluorescence microscopy, immunofluorescence to locate receptors and enzymes involved in this response. Our results demonstrated that perivascular adipose tissue induces an anti-contractile effect in endothelium-independent manner and involves Mas and AT2 receptors participation with subsequent PI3K/Akt pathway activation. This pathway culminated with nitric oxide and hydrogen peroxide production by neuronal nitric oxide synthase, being hydrogen peroxide most relevant for the anti-contractile effect of perivascular adipose tissue. CONCLUSION: For the first time in the literature, our results show the presence of Mas and AT2 receptors, as well as, nitric oxide synthase on perivascular adipose tissue. Furthermore, our results show the involvement of Mas and AT2 receptors and consequently nitric oxide synthase activation in the anti-contractile effect exerted by perivascular adipose tissue.