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Vascular insulin signaling has not changed in perivascular adipose tissue (PVAT) of LDLr knockout mice. Protein expression of IRS-1 (A), p85 subunit of PI3K (B), p-Akt/Akt ratio (C), and p-ERK/ERK ratio (D) in PVAT from wild-type (WT) and LDLr knockout (LDLr-KO) mice. Representative blots are shown at the top of the graphs.
Source publication
Background: Endothelial dysfunction plays a pivotal role in the initiation of atherosclerosis. Vascular insulin resistance might contribute to a reduction in endothelial nitric oxide (NO) production, leading to impaired endothelium-dependent relaxation in cardiometabolic diseases. Because perivascular adipose tissue (PVAT) controls endothelial func...
Citations
... ED is characterized by a decrease in the bioavailability of the vasodilator -NO, and an increase in the level of vasoconstrictor substances (ROS, thromboxanes, lipoperoxides, prostaglandins F2α). This imbalance leads to vasoconstriction, leukocyte attach ment, inflammatory reactions in the vascular wall, atherosclerosis and thrombosis [6,7,8]. It is known that the formation of ED in type 2 diabetes mellitus (T2DM) occurs against the background of a decrease in the bioavailability of NO. ...
... It is known that the formation of ED in type 2 diabetes mellitus (T2DM) occurs against the background of a decrease in the bioavailability of NO. Other factors that may contribute to ED in T2DM include decreased production of other dilating factors, increased production of vasoconstrictors (ROS, lipid peroxidation products of fatty acids and phospholipids, cy totoxic metabolites of NO), and decreased sensitivity of vascular smooth muscle to vasodilators [6,7,9]. Oxidative stress not only leads to a decrease in the bioavailability of nitric oxide (NO) (due to its conversion to peroxynitrite), but also contributes to a de crease in the level of reduced thiols (glutathione, cysteine, etc.), which act as a carrier and protector of nitrogen monoxide [6,7]. ...
... Other factors that may contribute to ED in T2DM include decreased production of other dilating factors, increased production of vasoconstrictors (ROS, lipid peroxidation products of fatty acids and phospholipids, cy totoxic metabolites of NO), and decreased sensitivity of vascular smooth muscle to vasodilators [6,7,9]. Oxidative stress not only leads to a decrease in the bioavailability of nitric oxide (NO) (due to its conversion to peroxynitrite), but also contributes to a de crease in the level of reduced thiols (glutathione, cysteine, etc.), which act as a carrier and protector of nitrogen monoxide [6,7]. ...
Endothelial dysfunction is characterized by a decrease in the bioavailability of the vasodilator-nitric oxide (NO), and an increase in the level of vasoconstrictor substances. This imbalance leads to vasoconstriction, leukocyte attachment and inflammatory reactions in the vascular wall, atherosclerosis and thrombosis. The aim: to evaluate the role of adipose tissue elements in the regulation of parameters of the nitroxidergic system under hypoxia conditions. Materials and methods. The studies were carried out on 30 adult white male Wistar rats. All animals were ran domly assigned and divided into groups: a control group (15 rats), type 2 diabetes mellitus (T2DM) was induced in the animals of the second group (15 rats). Isolated fragments of the popliteal arteries (PA) and intrapulmonary artery (IPA) were cleared of perivascular adipose tissue (PVAT-) or left uncleaned (PVAT+) and cut into rings. The simulation of acute hypoxia with further study of medical agents were performed. Results. The PA and IPA with PVAT responded to acute hypoxia with vasoconstriction-an increase in the am plitude of contraction in the first and second phases, and after removing PVAT, they responded with a decrease in the maximum amplitude of contraction by 3.4 times in the 1 st phase and an increase in amplitude by 1.8 times in the 2 nd phase. Perfusion with Angiolin reduced 2 nd phase of HV of the PA and IPA. Adding a combination of Thiotriazoline and L-arginine (1:4) to a solution for perfusion of fragments of arteries of animals with T2DM, causes a significant increase in constrictor reactions in both the 1 st and 2 nd phases of HV, regardless of presence of perivascular adipose tissue. Conclusions. The presence of PVAT affects the HV of arteries, both in normal and in T2DM. The possibilities of ways of pharmacological modulation of the nitroxidergic system depending on the state of PVAT were determined.
... Thereby, impaired endothelial function has been shown to be an aggravating factor for cardiovascular diseases, including gestational hypertension [7]. Previous evidence suggests that under endothelial dysfunction, the body activates compensatory mechanisms, in which PVAT may be of extreme relevance [8]. PVAT-dependent vasodilation may also involve the action of ADRFs through the activation of potassium channels; thus, it is essential to study molecules that act through this pathway and that are synthesized by PVAT, such as sulfide hydrogen (H 2 S) [9]. ...
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.
... Recently, eNOS expression has been reported in cells other than endothelial cells in vitro and in vivo. In particular, eNOS expression and NO production have been detected in the adipocytes in aortic PVAT in both animal models Antioxidants 2023, 12, 1595 4 of 21 and human samples [58][59][60][61][62]. The expression of eNOS in PVAT highly varies among the anatomical localisations in the vascular system. ...
... PVAT dysfunction can be rescued by restoring the normal expression and function of eNOS. In mice lacking low-density lipoprotein receptors (Ldlrs), thoracic PVAT exhibited compensatorily increased eNOS expression and NO production, which protected against impaired vasodilatation responses to acetylcholine and insulin [60]. Standardised Crataegus extract WS ® 1442 is a dry extract from hawthorn leaves with flowers with antioxidative properties [146]. ...
Perivascular adipose tissue (PVAT) adheres to most systemic blood vessels in the body. Healthy PVAT exerts anticontractile effects on blood vessels and further protects against cardiovascular and metabolic diseases. Healthy PVAT regulates vascular homeostasis via secreting an array of adipokine, hormones, and growth factors. Normally, homeostatic reactive oxygen species (ROS) in PVAT act as secondary messengers in various signalling pathways and contribute to vascular tone regulation. Excessive ROS are eliminated by the antioxidant defence system in PVAT. Oxidative stress occurs when the production of ROS exceeds the endogenous antioxidant defence, leading to a redox imbalance. Oxidative stress is a pivotal pathophysiological process in cardiovascular and metabolic complications. In obesity, PVAT becomes dysfunctional and exerts detrimental effects on the blood vessels. Therefore, redox balance in PVAT emerges as a potential pathophysiological mechanism underlying obesity-induced cardiovascular diseases. In this review, we summarise new findings describing different ROS, the major sources of ROS and antioxidant defence in PVAT, as well as potential pharmacological intervention of PVAT oxidative stress in obesity.
... The anticontractile response induced by PVAT was absent when the aorta was incubated with an angiotensin-converting enzyme inhibitor, a Mas receptor antagonist, an angiotensin AT 2 receptor antagonist, and NOS inhibitors, thus suggesting the role of angiotensin II (ANG-II, acting through AT 2 receptors), ANG 1-7 (acting through Mas receptors), and NO signaling pathways (Dos Reis Costa et al., 2021). In low-density lipoprotein receptor (LDLr)-knockout mice (KO), the absence of PVAT impaired the relaxation induced by acetylcholine and insulin (Baltieri et al., 2018). Based on these findings, the authors proposed a protective role for PVAT in the initial phase of obesity to curb the associated atherosclerosis and ischemia and to preserve vascular function. ...
Background: The prostate gland is surrounded by periprostatic adipose tissue (PPAT) that can release mediators that interfere in prostate function. In this study, we examined the effect of periprostatic adipose tissue supernatant obtained from obese mice on prostate reactivity in vitro and on the viability of human prostatic epithelial cell lines.
Methods: Male C57BL/6 mice were fed a standard or high-fat diet after which PPAT was isolated, incubated in Krebs-Henseleit solution for 30 min (without prostate) or 60 min (with prostate), and the supernatant was then collected and screened for biological activity. Total nitrate and nitrite (NOx ⁻ ) and adenosine were quantified, and the supernatant was then collected and screened for biological activity. NOx ⁻ and adenosine were quantified. Concentration-response curves to phenylephrine (PE) were obtained in prostatic tissue from lean and obese mice incubated with or without periprostatic adipose tissue. In some experiments, periprostatic adipose tissue was co-incubated with inhibitors of the nitric oxide (NO)-cyclic guanosine monophosphate pathway (L-NAME, 1400W, ODQ), adenylate cyclase (SQ22536) or with adenosine A 2A (ZM241385), and A 2B (MRS1754) receptor antagonists. PNT1-A (normal) and BPH-1 (hyperplasic) human epithelial cells were cultured and incubated with supernatant from periprostatic adipose tissue for 24, 48, or 72 h in the absence or presence of these inhibitors/antagonists, after which cell viability and proliferation were assessed.
Results: The levels of NOx ⁻ and adenosine were significantly higher in the periprostatic adipose tissue supernatant (30 min, without prostate) when compared to the vehicle. A trend toward an increase in the levels of NOX was observed after 60 min. PPAT supernatant from obese mice significantly reduced the PE-induced contractions only in prostate from obese mice. The co-incubation of periprostatic adipose tissue with L-NAME, 1400W, ODQ, or ZM241385 attenuated the anticontractile activity of the periprostatic adipose tissue supernatant. Incubation with the supernatant of periprostatic adipose tissue from obese mice significantly increased the viability of PNT1-A cells and attenuated expression of the apoptosis marker protein caspase-3 when compared to cells incubated with periprostatic adipose tissue from lean mice. Hyperplastic cells (BPH-1) incubated with periprostatic adipose tissue from obese mice showed greater proliferation after 24 h, 48 h, and 72 h compared to cells incubated with culture medium alone. BPH-1 cell proliferation in the presence of PPAT supernatant was attenuated by NO-signaling pathway inhibitors and by adenosine receptor antagonists after 72 h.
Conclusion: NO and adenosine are involved in the anticontractile and pro-proliferative activities of periprostatic adipose tissue supernatant from obese mice. More studies are needed to determine whether the blockade of NO and/or adenosine derived from periprostatic adipose tissue can improve prostate function.
... Long-term high insulin leads to impairment of insulin signaling pathway at the level of IRS-1, resulting in decreased glucose transport/ phosphorylation/metabolism, abnormal NO metabolism mechanism of vascular endothelial cells and smooth muscle cells, and inhibition of eNOS [37]. The down-regulation of eNOS leads to the reduction of NO biological activity, and its biological effects such as anti-infection, anti-oxidative stress, and inhibition of smooth muscle proliferation and migration are correspondingly weakened [38]; the reduction of NO bioavailability is accompanied by elevation in angiotensin II and free fatty acids, exacerbating levels of oxidative stress that can further worsen endothelial function [39][40][41]. In addition, the accumulated free radicals generated by lipid peroxidation in turn inhibit the bio-utilization of NO and promote the release of inflammatory factors and adhesion molecules [42]. ...
Objective
To date, therapies for endothelial dysfunction have primarily focused on ameliorating identified atherosclerosis (AS) risk factors rather than explicitly addressing endothelium-based mechanism. An in-depth exploration of the pathological mechanisms of endothelial injury was performed herein.
Methods
Aortic caveolin 1 (Cav1) knockdown was achieved in mice using lentivirus, and AS was induced using a high-fat diet. Mouse body weight, blood glucose, insulin, lipid parameters, aortic plaque, endothelial injury, vascular nitric oxide synthase (eNOS), injury marker, and oxidative stress were examined. The effect of Cav1 knockdown on the content of PKCzeta and PI3K/Akt/eNOS pathway–related protein levels, as well as PKCzeta binding to Akt, was studied. ZIP, a PKCzeta inhibitor, was utilized to treat HUVECs in vitro, and the effect of ZIP on cell viability, inflammatory response, oxidative stress, and Akt activation was evaluated.
Results
Cav1 knockdown had no significant effect on body weight or blood glucose in mice over an 8-week period, whereas drastically reduced insulin, lipid parameters, endothelial damage, E-selectin, and oxidative stress and elevated eNOS levels. Moreover, Cav1 knockdown triggered decreased PKCzeta enrichment and the activation of the PI3K/Akt/eNOS pathway. PKCzeta has a positive effect on cells without being coupled by Cav1, and ZIP had no marked influence on PKCzeta-Akt binding following Cav1/PKCzeta coupling.
Conclusion
Cav1/PKCzeta coupling antagonizes the activation of PI3K on Akt, leading to eNOS dysfunction, insulin resistance, and endothelial cell damage.
... The role of PVAT can also be preventive against endothelial dysfunction in a pro-oxidative state of high cholesterol as observed in mice without LDL receptors. The method of protection in this model involves increases in eNOS which leads to elevated NO release by PVAT, assuring a normal relaxation of blood vessels and prevention of endothelial dysfunction [4]. ...
People
with sedentary lifestyles engage in minimal or no physical activity. A sedentary lifestyle promotes dysregulation of cellular redox balance, diminishes mitochondrial function, and increases NADPH oxidase activity. These changes collectively increase cellular oxidative stress, which alters endothelial function by oxidizing LDL-C, reducing NO production, and causing eNOS uncoupling. Reduced levels of nitric oxide (NO) leads to vasoconstriction, vascular remodeling, and vascular inflammation. Exercise modulates reactive oxygen species (ROS) to modify NRF2-KEAP signaling, leading to the activation of NRF2 to alleviate oxidative stress. While regular moderate exercise activates NRF2 through ROS production, high-intensity intermittent exercise stimulates NRF2 activation to a greater degree by reducing KEAP levels, which can be more beneficial for sedentary individuals. We review the damaging effects of a sedentary lifestyle on the vascular system and the health benefits of regular and intermittent exercise.
... While the expression of iNOS in PVAT is only induced in pathological conditions [82], and the expression of nNOS in PVAT is controversial [83], the expression of eNOS in thoracic aortic PVAT has recently been demonstrated by various groups. Gene and protein expressions of eNOS in PVAT have been detected [6,84]. Using immunohistochemistry, eNOS can be stained in both adipocytes and endothelial cells of the capillaries and vasa vasorum in aortic PVAT [6,85]. ...
... In PVAT-adhered, endothelium-denuded rat mesenteric arteries, inhibition of eNOS significantly enhances NE-induced contraction, indicating that eNOS in PVAT contributes to the vascular NO production, while the anticontractile effect of PVAT is, at least partly, independent of the endothelium [33,90]. In low-density lipoprotein receptor (Ldlr) knockout mice, the thoracic aortic PVAT shows significant upregulation of eNOS expression and NO production, which protects against impaired vasorelaxation to acetylcholine and insulin [84]. In a very recent clinical study, the authors demonstrated PVAT as a predominant source of NO in human vasculature in a no-touch saphenous vein grafts (NT-SVGs) coronary artery bypass model [91]. ...
Perivascular adipose tissue (PVAT) is a special type of ectopic fat depot that adheres to most vasculatures. PVAT has been shown to exert anticontractile effects on the blood vessels and confers protective effects against metabolic and cardiovascular diseases. PVAT plays a critical role in vascular homeostasis via secreting adipokine, hormones, and growth factors. Endothelial nitric oxide synthase (eNOS; also known as NOS3 or NOSIII) is well-known for its role in the generation of vasoprotective nitric oxide (NO). eNOS is primarily expressed, but not exclusively, in endothelial cells, while recent studies have identified its expression in both adipocytes and endothelial cells of PVAT. PVAT eNOS is an important player in the protective role of PVAT. Different studies have demonstrated that, under obesity-linked metabolic diseases, PVAT eNOS may be even more important than endothelium eNOS in obesity-induced vascular dysfunction, which may be attributed to certain PVAT eNOS-specific functions. In this review, we summarized the current understanding of eNOS expression in PVAT, its function under both physiological and pathological conditions and listed out a few pharmacological interventions of interest that target eNOS in PVAT.
... In a separate set of experiments, preparations were pre-incubated with either 10 µM mito-tempol (30 min), 0.3 µM SR 59230A (30 min), or 30 µM pyrogallol (20 min) before the addition of noradrenaline. Responses were calculated as a percentage of the contraction induced by either noradrenaline or phenylephrine, taken as 100% [36]. ...
Several studies demonstrate the beneficial effects of dietary flavonoids on the cardiovascular system. Since perivascular adipose tissue (PVAT) plays an active role in the regulation of vascular tone in both health and diseases, the present study aimed to assess the functional interaction between PVAT and flavonoids in vitro on rat aorta rings. Several flavonoids proved to display both antispasmodic and spasmolytic activities towards noradrenaline-induced contraction of rings deprived of PVAT (-PVAT). However, on PVAT-intact (+PVAT) rings, both actions of some flavonoids were lost and/or much decreased. In rings-PVAT, the superoxide donor pyrogallol mimicked the effect of PVAT, while in rings+PVAT the antioxidant mito-tempol restored both activities of the two most representative flavonoids, namely apigenin and chrysin. The Rho-kinase inhibitor fasudil, or apigenin and chrysin concentration-dependently relaxed the vessel active tone induced by the Rho-kinase activator NaF; the presence of PVAT counteracted apigenin spasmolytic activity, though only in the absence of mito-tempol. Similar results were obtained in rings pre-contracted by phenylephrine. Finally, when β3 receptors were blocked by SR59230A, vasorelaxation caused by both flavonoids was unaffected by PVAT. These data are consistent with the hypothesis that both noradrenaline and apigenin activated adipocyte β3 receptors with the ensuing release of mitochondrial superoxide anion, which once diffused toward myocytes counteracted flavonoid vasorelaxant activity. This phenomenon might limit the beneficial health effects of dietary flavonoids in patients affected by either obesity and/or other pathological conditions characterized by sympathetic nerve overactivity.
... The vascular endothelium plays a central role in atherogenesis, specifically, existing literature describes endothelial damage and dysfunction as a cause of vascular inflammation and plaque formation in mouse models of atherosclerosis and hyperlipidemia [4]. In addition, perivascular adipose tissue (PVAT) has earned recognition as a modulator of vascular functions including constriction, relaxation and remodeling via active secretion of adipocytokines including adiponectin, but also pro-inflammatory mediators such as IL-1β and IL-6 [5][6][7][8]. ...
... Recently, a closely related study investigated the protective role of PVAT in 4-months old low-density lipoprotein receptor knockout (LDLr − /− ) mice, which was considered a model of early-stage hypercholesterolemia and atherosclerosis [4]. The authors found that LDLr − /− thoracic aortic PVAT rescued mild endothelial dysfunction, expressed more eNOS than control PVAT, and produced NO in situ [4]. ...
... Recently, a closely related study investigated the protective role of PVAT in 4-months old low-density lipoprotein receptor knockout (LDLr − /− ) mice, which was considered a model of early-stage hypercholesterolemia and atherosclerosis [4]. The authors found that LDLr − /− thoracic aortic PVAT rescued mild endothelial dysfunction, expressed more eNOS than control PVAT, and produced NO in situ [4]. Moreover, 20-week old ApoE − /− rats receiving a Western-type diet exhibited only modest early atherosclerotic characteristics [10]. ...
Background and aims
Atherosclerosis is a major contributor to global mortality and is accompanied by vascular inflammation and endothelial dysfunction. Perivascular adipose tissue (PVAT) is an established regulator of vascular function with emerging implications in atherosclerosis. We investigated the modulation of aortic relaxation by PVAT in aged rats with apolipoprotein E deficiency (ApoE−/−) fed a high-fat diet as a model of early atherosclerosis.
Methods and results
ApoE−/− rats (N = 7) and wild-type Sprague-Dawley controls (ApoE+/+, N = 8) received high-fat diet for 51 weeks. Hyperlipidemia was confirmed in ApoE−/− rats by elevated plasma cholesterol (p < 0.001) and triglyceride (p = 0.025) levels. Early atherosclerosis was supported by increased intima/media thickness ratio (p < 0.01) and ED1-positive macrophage influx in ApoE−/− aortic intima (p < 0.001). Inflammation in ApoE−/− PVAT was characteristic by an increased [18F]FDG uptake (p < 0.01), ED1-positive macrophage influx (p = 0.0003), mRNA expression levels of CD68 (p < 0.001) and IL-1β (p < 0.01), and upregulated iNOS protein (p = 0.011). The mRNAs of MCP-1, IL-6 and adiponectin remained unchanged in PVAT. Aortic PVAT volume measured with micro-PET/CT was increased in ApoE−/− rats (p < 0.01). Maximal endothelium-dependent relaxation (EDR) to acetylcholine in ApoE−/− aortic rings without PVAT was severely impaired (p = 0.012) compared with controls, while ApoE−/− aortic rings with PVAT showed higher EDR than controls. All EDR responses were blocked by L-NMMA and the expression of eNOS mRNA was increased in ApoE−/− PVAT (p = 0.035).
Conclusion
Using a rat ApoE−/− model of early atherosclerosis, we capture a novel mechanism by which inflammatory PVAT compensates severe endothelial dysfunction by contributing NO upon cholinergic stimulation.
... Hypercholesterolemic low-density lipoprotein receptor (LDLr) knockout mice exhibited the rescue of vascular relaxation in thoracic aortas with intact PVAT compared with PVAT-denuded aortas. This effect, however, was not associated with alterations of adiponectin expression [98]. This effect may be related to adipocyte β3-adrenoreceptor activation, which was shown to mediate vasorelaxation-induced norepinephrine release [84]. ...
Studies of adipose tissue biology have demonstrated that adipose tissue should be considered as both passive, energy-storing tissue and an endocrine organ because of the secretion of adipose-specific factors, called adipokines. Adiponectin is a well-described homeostatic adipokine with metabolic properties. It regulates whole-body energy status through the induction of fatty acid oxidation and glucose uptake. Adiponectin also has anti-inflammatory and antidiabetic properties, making it an interesting subject of biomedical studies. Perivascular adipose tissue (PVAT) is a fat depot that is conterminous to the vascular wall and acts on it in a paracrine manner through adipokine secretion. PVAT-derived adiponectin can act on the vascular wall through endothelial cells and vascular smooth muscle cells. The present review describes adiponectin’s structure, receptors, and main signaling pathways. We further discuss recent studies of the extent and nature of crosstalk between PVAT-derived adiponectin and endothelial cells, vascular smooth muscle cells, and atherosclerotic plaques. Furthermore, we argue whether adiponectin and its receptors may be considered putative therapeutic targets.
