## 2 Characteristics of PVAT
PVAT macrophages are associated with atherosclerosis in the adjacent artery, but the anti-inflammatory M2 macrophages are more abundant, which suggests desensitization of the inflammatory response in PVAT in advanced CAD [17]. In perivascular adipocytes, the secretion of the MCP-1/CCL2 protein, with an important role in the pathogenesis of atherosclerosis, is up to 40-fold higher than in perirenal and subcutaneous adipocytes. Again, anti-inflammatory factors, such as adrenomedullin, are also synthesized by PVAT, suggesting a simultaneous protective role for the PVAT on the adjacent vessels [14]. This balance between protective and detrimental effects exerted by PVAT on atherosclerosis could be disturbed by gut-derived antigens such as lipopolysaccharideadiers, dietary lipids,hypoxia, or mechanical stress, which have a direct impact on inflammation and the accumulation of proinflammatory macrophages in adipose tissues. In vivo animal models have shown that in obesity proinflammatory signaling in perivascular mesenchymal cells has a key role in chronic inflammation of white adipose tissues. TLR4 signaling in perivascular stromal cells mediates proinflammatory macrophage accumulation. Fibro-inflammatory progenitors, a specialized subpopulation of perivascular cells activated during metabolic inflammation, modulate macrophage homeostasis [18]. Ghrelin acts directly on adipocytes to stimulate adipogenesis through preadipocyte differentiation and antagonism of isoproterenol-induced lipolysis. The expression of ghrelin receptors in adipocytes is upregulated during preadipocyte differentiation [19]. Ghrelin stimulates angiogenesis in the adipose tissue by inhibiting bone morphogenic protein-4 (BMP-4), which regulates adipogenic cell precursors differentiation, bone morphogenic protein-7 (BMP-7), involved in the formation of brown adipose tissue, and VEGF [20]. Ghrelin inhibits sympathetic effects to brown adipose tissue and impairs the intracellular breakdown of triglycerides into free fatty acids [21], leading to weight gain. Although ghrelin acts as a neurotransmitter that modulates sympathetic activity to white and brown adipose tissue, its role on lipid synthesis and mobilization and adipokine release in PVAT requires further investigation. Lipid storage promotes vascular inflammation. However, high ghrelin levels improve outcomes in early atherosclerosis [22; 23]. This anti-atherosclerotic effect is attributed to a balance between macrophage cholesterol uptake and efflux regulated by ghrelin and its GHS-R1a receptor. Ghrelin stimulates the expression of the adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARy) from adipocytes, which is associated with enhanced cholesterol efflux by macrophages and lower risk of atherosclerotic lesions [24]. Ghrelin protects against atherosclerosis by inhibiting the GRP78/CHOP/caspase-12 signaling pathway which involves endoplasmic reticulum stress-related proteins [25; 26]. Gut microbiome products, such as trimethylamine-N-oxide are involved in atherogenesis. Ghrelin shows inverse correlations with trimethylamine N-oxide [27]. The atherosclerotic process may be accelerated by endothelial cell apoptosis which causes deposition of lipids and fibrous elements on the arterial wall [28]. The inhibition of hyperglycemia-induced apoptosis in endothelial cells and vascular smooth muscle cells (VSMC) is mediated by GHS-R1a receptors. Ghrelin directly inhibits VSMC apoptosis and proliferation by activation of the cAMP/PKA pathway [29]. The stimulation of intracellular signaling pathways that inhibit apoptosis is achieved by phosphorylation and activation of ERK1/2 and PIJK/Akt [30; 31; 32; 33]. The inhibition of plaque angiogenesis caused by oxidized low-density lipoprotein is also mediated by GHS-R1a receptors. FGF-2, a modulator of angiogenesis that mediates atherosclerotic neovascularization, is inhibited by ghrelin in vitro and in vivo.