Obesity is now known as an epidemic worldwide, which has become a global public health concern and burden [1]. Obesity is a well-known risk factor for cardiovascular disorders like endothelial dysfunction, atherosclerosis, hypertension, and coronary artery disease [2]. In 1991, the pioneering work of Soltis and Cassis suggested that perivascular adipose tissue (PVAT), a functional specialised ectopic fat depot, acts as a critical modulator of vascular physiology and pathology [3]. Indeed, accumulating data from both clinical and experimental studies demonstrate that the dysfunction of PVAT is a causal link between metabolic diseases and cardiovascular complications ^[4][5][6][4,5,6]. Most blood vessels, including large arteries and veins, small and resistance vessels, and skeletal muscle microvessels, are surrounded by PVAT [7]. PVAT stays in close proximity to the tunica adventitia of blood vessels, serving as a pivotal endocrine and/or paracrine tissue that maintains cardiovascular and metabolic homeostasis. PVAT contains both white and brown adipocytes [8]. Apart from adipocytes, endothelial cells, fibroblasts, immune cells extracellular matrix, and adrenergic nerves endings are also present in PVAT. Depending on the vessel type and region, PVAT may have different compositional, phenotypic, and functional aspects throughout the vascular system ^[9][10][9,10]. The phenotype of PVAT has been extensively reviewed ^{[11][12][13][14][15]}[11,12,13,14,15]. In recent decades, revealing the crosstalk between blood vessels and PVAT has become a particular interest in the field of vascular biology. Apart from its structural and mechanical roles in vascular support, PVAT is actively involved in vascular homeostasis and contributes to vascular dysfunction associated with cardiovascular and metabolic diseases.

A healthy PVAT Is known to exert anticontractile effects on blood vessels in both animal models and humans ^[16][17][16,17]. PVAT, as a endocrine and/or paracrine tissue, regulates vascular function by releasing various vaso-active factors, including adipokines, chemokines, cytokines, hydrogen sulphide (H₂S), nitric oxide (NO), and reactive oxygen species (ROS) [7]. These vasoactive substances could enter the endothelial layer of the vessel wall by diffusion or via the vasa vasorum or the small media conduit networks that connect the media with the adventitia layer ^[9][18][19][9,18,19]. These factors produced from PVAT include proinflammatory and anti-inflammatory molecules, which take part in various cellular processes, including smooth muscle proliferation and migration, vascular tone, inflammation, and oxidative stress in the vasculature ^[10][20][10,20].

Depending on the ‘health status’ of PVAT, it may elicit beneficial or harmful effects on the vasculature [21]. In obesity, PVAT becomes dysfunctional and exerts detrimental effects on the blood vessels ^[4][5][6][4,5,6]. The ‘obesity triad’ is proposed as the central mechanism in obesity-induced PVAT dysfunction [7]. The obesity triad consists of the interactions among PVAT hypoxia, inflammation, and oxidative stress. Among the triad, oxidative stress is a pivotal pathophysiological process in cardiovascular and metabolic complications, including obesity, type 2 diabetes, and hypertension. As oxidative stress is a key feature of hypertension, it is also known to regulate redox-dependent inflammatory molecules [22]. Normally, homeostatic ROS act as crucial secondary messengers in different signalling pathways of both innate and adaptive immune responses [23].

2. PVAT Oxidative Stress in Obesity

Obesity is a condition of excessive fat mass and subclinical inflammation. The prevalence of obesity has doubled worldwide over the past few decades, as well as the concomitant increase in obesity-associated cardiovascular diseases ^[24][91]. Obesity is a major risk factor for cardiovascular and metabolic diseases, including type 2 diabetes, insulin resistance, and hypertension ^[25][92]. In fact, endothelial dysfunction is not always evident in obese patients in vitro, although they have a higher risk of developing hypertension, cardiomyopathy, and stroke. Various studies have demonstrated that the anti-contractile effects of PVAT are attenuated in obesity ^[4][26][27][4,58,76]. Indeed, PVAT dysfunction, but not obesity itself, plays an important role in obesity-induced vascular disorders. In mice aortas, the responses to vasodilators were not different between the aortas isolated from obese and lean mice, while vasodilator responses were attenuated in the aortas isolated from obese mice when PVAT was attached ^[26][28][58,62]. In addition, mesenteric arteries incubated with thoracic PVAT from HFD-fed rats showed diminished endothelium-dependent relaxation compared to those incubated with thoracic PVAT from NCD-fed rats ^[29][93]. This suggests that the detrimental effects of obesity do not directly influence the intrinsic vascular reactivity but rather the function of PVAT and PVAT dysfunction are closely related to the development of obesity-associated vascular complications. PVAT function in modulating vascular haemostasis has been extensively reviewed ^[11][12][11,12]. Under normal conditions, the physiological level of ROS is crucial to maintaining vascular homeostasis and is responsible for vascular responses, and excess ROS are antagonised by several antioxidant enzyme systems in PVAT, as mentioned above ^[30][31][49,74]. Pro-inflammatory and pro-oxidative states in PVAT significantly altered the anti-contractile effects and functions of PVAT under obese conditions ^[32][94]. For example, during obesity, H₂O₂ might act as a PVAT-derived contractile factor ^[27][76]. PVAT dysfunction leads to the imbalance of PVAT-derived vasoactive factors and affects vascular function ^[33][95]. In obesity, the mass of PVAT is increased and adipocytes become hypertrophy, resulting in a shift to white adipose tissue-like characteristics of PVAT, accompanied by deformed mitochondria ^[29][93]. Chronic inflammation is evident in obese PVAT, characterised by the infiltration of dendritic cells and macrophage and the upregulation of inflammatory cytokines, including monocyte chemoattractant protein-1 (MCP-1), tumour necrosis factor alpha (TNF-α), IL-6, and the adipokine leptin ^[34][35][96,97]. On the other hand, the expression of adiponectin, an anti-inflammatory adipokine, is reduced in obese PVAT ^[36][98]. Inflammation in PVAT also stimulates the generation of O₂⁻ and H₂O₂ by NOX, which promotes the pro-contractile activity of the vessel wall. Also, hypertrophic adipocytes may exhibit insufficient blood perfusion, which leads to local hypoxia in PVAT. The expression of the key modulator of hypoxia, hypoxia-inducible factor alpha (HIF-1α), is increased in the adipose tissues of obese subjects ^[37][99]. HIF-1α can stimulate the production of inflammatory mediators, such as TNF-α and IL-6, and suppress the expression of adiponectin from PVAT ^[38][100]. In the small mesenteric arteries of healthy Wistar rats, incubation with TNF-α and IL-6 led to the loss of anti-contractile effects of mesenteric PVAT, whereas the induction of hypoxia led to inflammation and dysfunction of mesenteric PVAT [17]. This hypoxia-induced mesenteric PVAT dysfunction was restored by treatment with either IL-6 antibody, TNF-α antibody, or exogenous catalase and SOD in vitro [17]. HFD-induced obese mice with TNF-α receptor knockdown had reduced H₂O₂ generation in PVAT and sensitivity to phenylephrine(PE)-induced vasocontraction, suggesting that oxidative stress is crucial to the pro-contractile shift of PVAT ^[27][76]. In addition, the combination of inflammation and oxidative stress may create a vicious cycle that further generates genetic and cardio-metabolic factors, leading to atherogenesis ^[39][101]. Therefore, oxidative stress in PVAT is a critical link between metabolic diseases and cardiovascular complications. Various studies have also demonstrated that obesity-induced PVAT dysfunction is associated with increased ROS generation from different sources ^{[4][26][27][35]}[4,58,76,97]. ob/ob mice showed low activity of GPX and the upregulation of gamma-glutamylcysteine synthetase (γ-GCS), resulting in high glutathione content in adipose tissues ^[40][79]. In a study, the expression of SOD2 was significantly reduced and catalase expression was increased in the PVAT from obese mice. Interestingly, the SOD activity was increased, while there was no change in the catalase activity in PVAT. These data suggest a compensatory mechanism for increased ROS in obese PVAT ^[27][76]. The thoracic PVAT of obese mice lost its anti-contractile effect and became dysfunctional, which was associated with increased levels of O₂⁻ and H₂O₂ detect by DHE, Amplex red, and lucigenin ^[27][76]. An excess of mitochondria-derived ROS may be contribution by the oxidative stress in thoracic PVAT, as evidenced by a significant reduction in the O₂ consumption rate and the downregulation of UCP-1 and SOD2 in this tissue ^[27][76]. In addition to mitochondrial ROS, eNOS uncoupling also contributes to oxidative stress in thoracic PVAT. In the thoracic PVAT of obese mice, increased arginase activity was detected, which resulted in eNOS uncoupling, while L-arginine supplementation and arginase inhibition reversed the eNOS uncoupling ^[26][58]. In patients who underwent bariatric surgery, obese-induced PVAT dysfunction was restored by increased NO production and reduced TNF-α expression ^[41][102]. Moreover, thoracic PVAT-conditioned media from obese mice induced H₂O₂ production in the aortas isolated from control mice in vitro ^[34][96], suggesting that the secretome from obese PVAT could be pro-oxidant. The abdominal aortic PVAT of HFD-fed mice exhibited increased mass, adipocyte hypertrophy, and increased levels of O₂⁻ and H₂O₂ (evaluated by luminol chemiluminescence technique) compared to NCD-fed mice [4]. The abdominal PVAT from HFD-fed mice was dysfunctional and the abdominal aorta had impaired endothelium-dependent vasodilation in the presence of obese abdominal PVAT. NOX has been suggested as a source of ROS in obese abdominal aortic PVAT, which was evidenced by the upregulation of p67phox subunit [4]. In long-term HFD-fed rats, increased expressions of cytochrome c oxidase, GPx, and UCP-1 and a decreased expression of p22phox were detected in the aortic PVAT ^[42][103]. In the early stages of obesity, the overproduction of NO could preserve vascular function in mesenteric arteries ^[28][62]. However, in long-term HFD-induced obesity, mesenteric PVAT became dysfunctional and prooxidant, which was associated with increased O₂⁻ production, increased NOX activity, and reduced SOD activity ^[35][97]. HFD-fed mice also showed a reduced expression of SOD3 and glutathione levels in mesenteric PVAT ^[35][97]. The dysfunction of mesenteric PVAT in long-term HFD-induced obese mice was attenuated by incubation with exogenous sources of SOD and catalase, suggesting the generation of O₂⁻ and H₂O₂ in these dysfunctional mesenteric PVAT ^[43][84]. In addition, proteomic analysis of PVAT from gluteal fat biopsy revealed a downregulation of SOD1 and PRX-1 expression in obese individuals ^[43][84]. eNOS in PVAT plays an important role in obesity-induced vascular dysfunction ^[7][11][7,11], and rwesearchers have recently reviewed the detailed function of eNOS in PVAT both physiological and pathological conditions [12]. Various studies using HFD and/or genetically modified rodent models have demonstrated the pathophysiological role of eNOS expressed in PVAT in modulating vascular tone, function, and homeostasis, inflammation, and oxidative stress ^[26][44][45][58,104,105]. RWesearchers have previously shown evidence of PVAT eNOS dysfunction and eNOS uncoupling in mice with HFD-induced obesity ^[26][58]. At the early phase of HFD feeding, there was adaptive NO overproduction from mesenteric PVAT in C57BL/6J mice ^[28][62], while the expression of eNOS was reduced after long-term HFD feeding in the mesenteric PVAT of obese rats ^[46][106] and in the thoracic PVAT of obese mice ^[35][97]. The basal production of NO was reduced in the small arteries of obese patients compared to non-obese subjects, while this reduction was only evident in PVAT-adhered and not in PVAT-removed arteries ^[47][59]. The upregulation of arginase in obese PVAT reduces the bioavailability of L-arginine for NO production and leads to the uncoupling of eNOS ^[48][107], which in turn produces O₂⁻ and increases oxidative stress in PVAT ^[26][58]. Macrophages represent the key modulators of oxidative stress and inflammation in PVAT. The upregulation of IL-6 and MCP-1 levels lead to the recruitment of monocytes and macrophage in PVAT and the subsequent pathology of obesity-induced vascular complications ^[49][50][51][108,109,110]. Also, a reduced adiponectin level in obese PVAT was associated with increased macrophage infiltration ^[52][111]. In obese individuals, mineralocorticoid receptors (MR) are activated and their ligand aldosterone is significantly increased ^[53][112]. Aldosterone is known to activate NOX ^[54][113] and induce eNOS uncoupling ^[55][114]. The upregulation of MR increased H₂O₂ generation in adipocytes in vitro ^[56][115] and a blockade of MR prevented both mitochondrial and PVAT dysfunction in obesity ^[57][116]. MR may participate in PVAT dysfunction through the modulation of mitochondrial function ^[57][116]. Also, MR activation in PVAT macrophages may play a critical role in the pathogenesis of obesity-induced vascular dysfunction, as demonstrated by the beneficial effects in myeloid MR KO mice ^[58][117]. Therefore, MR activation is especially interesting in the context of obesity-related cardiovascular and metabolic diseases. The aldoketo reductase super-family catalyses the generation of sorbitol in the polyol metabolic pathway of glucose metabolism. Aldose reductase, a member of the super-family, may deplete the antioxidant glutathione system due to the scavenging of NADPH, which in turn increases ROS production ^[59][118]. In a rat model of type 2 diabetes, the aortic PVAT exhibited increased levels of markers of oxidative stress, including malonaldehyde and aldose reductase activity, which were associated with reduced antioxidant defence ^[51][110]. Angiotensin II (Ang II) is the key component of the renin–angiotensin–aldosterone system (RAAS), which has been extensively studied in vascular biology. Ang II mediates the PVAT-associated contractile response to perivascular neuronal excitation ^[60][119], while adipocyte RAAS is involved in adipogenesis and adipose tissue mass ^[61][120]. The upregulation of Ang II during obesity may lead to adipose tissue dysfunction and induce ROS production in PVAT ^[62][121]. In a rat model of heart failure, oxidative stress (measured by DHE fluorescence) and reduced NO bioavailability have been shown to be associated with the impaired anti-contractile effect of thoracic PVAT ^[63][122]. In a recent RNA sequencing study, the responses of different PVAT to Ang II have been investigated ^[64][123]. Upon stimulation by Ang II, abdominal aortic PVAT showed a significant downregulation of mitochondrial genes in oxidative phosphorylation and brown adipocyte markers and an upregulation of inflammatory markers. In addition, Ang II induced even more significant inflammation in both ascending and descending thoracic aortic PVAT ^[64][123]. Together, these targets may emerge as possible mediators of oxidative stress in PVAT during obesity, and further studies are warranted to elucidate the mechanisms (Figure 1).