Perivascular Adipose Tissue as a Target for Antioxidant Therapy for Cardiovascular Complications

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  Figure 1. The crosstalk between perivascular adipose tissue (PVAT) and the blood vessel modulates vascular function. PVAT releases vasoactive molecules. H2S is synthesized in PVAT and induces vascular smooth muscle cell (VSMC) hyperpolarization. Leptin activates eNOS and stimulates H2S production, which lead to endothelium-dependent vasodilatation. H2S released from endothelium and PVAT functions as an endothelium-derived hyperpolarizing factor (EDHF) and activates endothelial K+ channels. The resulting hyperpolarization of endothelial cells can be transmitted to VSMC. NO and H2O2 released from PVAT can elicit vasodilatation by activating soluble guanylyl cyclase (sGC). Adiponectin produced by PVAT stimulates NO production in PVAT and in endothelial cells and induces VSMC hyperpolarization. Ang 1–7 acts on endothelial cells and stimulates endothelial NO production. Vasodilating prostaglandins released from PVAT can act on VSMC and stimulate vasorelaxation. Reactive oxygen species (ROS) produced from nicotinamide adenine dinucleotide phosphate (NADPH) oxidases in PVAT can cause contractile response in VSMC via the mitogen-activated protein kinase/extracellular signal-regulated kinase…

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  Figure 2. Mechanisms of PVAT dysfunction in diet-induced obesity. High-fat diet (HFD)-induced adipocyte hypertrophy leads to hypoxia and the production of pro-inflammatory cytokines and chemokines, the activation of NADPH oxidases, and the downregulation of antioxidant enzymes (e.g., superoxide dismutase and peroxiredoxin-1) and non-enzymatic antioxidants (e.g., glutathione). Infiltrating immune cells potentiate PVAT inflammation and oxidative stress. Chronic hyperleptinaemia leads to vascular leptin resistance (loss of leptin-induced vasodilatation) and the potentiation of PVAT inflammation. Long-term obesity decreases PVAT H2S production by downregulating CSE expression. The upregulation of arginases leads to L-arginine deficiency and eNOS uncoupling (enhanced superoxide production and reduced NO production by eNOS). PVAT adiponectin expression is reduced in obesity, likely due to a downregulation of PPARγ. Normally, NO stimulates adiponectin secretion and adiponectin increases PVAT NO production. This positive feedback mechanism is impaired in obesity. CSE, cystathionine gamma-lyase; H2S, hydrogen sulphide; PPARγ, peroxisome proliferator-activated receptors gamma; eNOS, endothelial…

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  Figure 3. Summary of oxidative stress in the pathophysiology of PVAT dysfunction. During aging or diet-induced obesity, oxidative stress is significantly increased in PVAT. Dysfunctional PVAT promotes cardiovascular diseases via the crosstalk with the underlying vascular cells, including the endothelium and VSMC under physiological and pathological conditions. Reversing the shift of PVAT towards WAT-like during the development of obesity and aging might be a crucial strategy to maintain a healthy vasculature. The potential use of antioxidant or targeting oxidative stress can be novel therapeutic target for PVAT-related cardiovascular complications. MR, mineralocorticoid receptor; Ang II, angiotensin II; DPP-IV, dipeptidyl peptidase-IV; H2S, hydrogen sulphide; GLP-1, glucagon-like peptide-1; eNOS, endothelial nitric oxide synthase; SIRT1, sirtuin 1; PVRF, PVAT-derived relaxing factors; PVCF, PVAT-derived contracting factors; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PPARγ, peroxisome proliferator-activated receptors gamma.

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  Figure 4. The potential use of antioxidants or targeting oxidative stress can be novel therapeutic targets for PVAT-related cardiovascular complications. It is important to maintain a physiological ROS level for adipogenic differentiation. Reducing oxidative stress and reversing the shift of PVAT towards WAT-like during the development of obesity and aging might be a crucial strategy to improve PVAT function. Detailed research is needed to dissect the molecular mechanisms of how oxidative stress modulates mitochondrial biogenesis in PVAT. DPP-IV, dipeptidyl peptidase-IV; H2S, hydrogen sulphide; GLP-1, glucagon-like peptide-1; eNOS, endothelial nitric oxide synthase; SIRT1, sirtuin 1; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PPARγ, peroxisome proliferator-activated receptors gamma; NOX, nicotinamide adenine dinucleotide phosphate oxidase; CB1, cannabinoid receptor type 1; AT1, angiotensin receptor type 1; ACE, angiotensin converting enzyme.