The impact of CRS on vascular function is not only limited to the ECs but also to VSMCs, which are the predominant cell type found in the arterial wall and are essential for the structural and functional integrity of the vessel. Diabetes increases PKC activity, NF-kappaB (NF-κΒ) production, and generation of oxygen-derived free radicals in VSMCs and heightens migration of VSMCs into atherosclerotic lesions, where they replicate and produce extracellular matrix—important steps in mature lesion formation [28]. Dysregulation of VSMC function is exacerbated by impairments in SNS function. Studies from the Zucker obese insulin-resistant rat have shown that VSMCs from these rats manifested greater concentrations of ROS and impaired activation of the NO/cGMP/protein kinase G (PKG) pathway when compared to VSMC from the lean, insulin-sensitive Zucker rats [29]. Our recent data also showed excessive serine phosphorylation of insulin receptor substrate (IRS-1) as a key mechanism underlying cellular IR in VSMCs. Furthermore, after treatment with aldosterone or Ang II, VSMCs show increased activation of p70 S6 kinase 1 signaling pathway, increased proteasome degradation of IRS-1, and attenuated insulin-induced Akt phosphorylation and glucose uptake [30]. These observations provide a biochemical basis to the IR in VSMCs in the development of AD.

Studies conducted in the United States have revealed that calcium deposits in arterial walls are reported in nearly 30 % of Americans over 45 years of age [31]. Vascular calcification risk factors are similar to those of atherosclerosis including hypertriglyceridemia, increased LDL, decreased HDL, obesity, and hypertension. It has also been shown that diabetes and renal failure contribute significantly to higher risk of accumulation of calcium depositions in the vessel wall [32]. Calcification of vessels reduces their elasticity, affecting hemodynamic parameters of the cardiovascular system. Vascular calcification is an active and complex process that involves numerous mechanisms responsible for calcium deposits in arterial walls. They lead to an increase in arterial stiffness and in pulse wave velocity, which in turn increases CVD morbidity and mortality. We have known that VSMCs can differentiate from a quiescent, contractile phenotype to a proliferative, synthetic phenotype following arterial injury and in atherosclerotic diseases [33]. Indeed, VSMCs are capable of osteoblast transdifferentiation in calcifying arteries [34]. Epidemiological data have shown that higher insulin levels in diabetes can independently predicate arterial calcification [35]. The mechanisms of insulin involved in arterial calcification in these clinical settings are still controversial. Furthermore, it has been demonstrated that insulin enhances the calcification of VSMCs in vitro [36]. In this regard, insulin promotes alkaline phosphatase activity, osteocalcin expression, and the formation of mineralized nodules in VSMCs by increased receptor expression of NF-κB ligand (RANKL) through extracellular signal-regulated protein kinases 1 and 2 (Erk ½) activation [37]. However, others suggest that insulin attenuated VSMC calcification induced by high phosphate conditions [38]. These contradictory results may be explained by different cell types or different experimental conditions.

Elastin is the most abundant protein in the walls of the arteries, which are subjected to pulsatile pressure generated by cardiac contraction. Matrix metalloproteinases (MMPs) have an important role in the degradation of elastin [39]. Recently, it was reported that in the arterial vasculature from chronic kidney disease patients, the presence of diabetes markedly upregulated MMP-2 and -9, and this adaption is strongly associated with elastic fiber degradation and AD. The increase in MMPs in diabetic vessels was also accompanied by pronounced generation of angiostatin, and the reduction of microvascular density was associated with impaired vasorelaxation [40]. In addition, the degradation of elastin also induces the overexpression of transforming growth factor beta (TGF-β). TGF-β1 not only plays an important role in osteoblast differentiation but also accelerates the calcification of VSMCs [39]. Meanwhile, hyperglycemia may cause changes in the type or structure of elastin and/or collagen in the arterial wall through nonenzymatic glycosylation of proteins that generate AGE. AGE may form irreversible cross-links between long-lived proteins such as collagen, leading to accumulation of stiffer molecules that are less susceptible to hydrolytic turnover [41]. These data confirm that the interaction among MMPs, elastin, collagen, and AGE plays a key role in the development of AD with CRS.

Mitochondria are essential for intermediary metabolism as well as energy production and normally provide more than 90 % of the cellular energy [42]. It has been established that mitochondrial respiratory chain function is responsible for energy metabolism and adenosine triphosphate (ATP) production through the tricarboxylic acid (TCA) cycle, coupling of oxidative phosphorylation (OXPHOS), and electron transfer [43]. Mitochondria dysfunction is recognized as playing a central role in the development of various abnormalities, including disturbed glucose homeostasis, IR, abdominal fat accumulation, dyslipidemia, hypertension, and associated cardiac and renal pathology. ROS production occurs mainly at complex I and complex III in mitochondria [44]. Under conditions of glucose and fatty acid overnutrition, nutrient overflow into cells prompts electrons transferring to oxygen without ATP production and further favors a state of increased ROS, which potentially leads to oxidative damage within mitochondria [45]. Therefore, ROS generated from mitochondria damages proteins, DNA, and lipid in membrane components, which result in mitochondrial dysfunction. Although this review is concerned with mitochondrial ROS, it should be recognized that the considerable amount of ROS is derived from outside of mitochondria, such as oxygen radicals from peroxisomal β-oxidation of fatty acids, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, arachidonic acid metabolism, microsomal P-450 enzymes, and prooxidant heme molecule [46].

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by an innate and adaptive immune system, which is composed of diverse cellular components including granulocytes, mast cells, monocytes, macrophages, dendritic cells (DCs), and natural killer cells [47]. Upon activation, partly in response to immunological stimuli from the local microenvironment as well as systemic circulation, macrophages polarize into classical (M1) or alternative (M2) phenotypes [48]. M1 macrophages are found in advanced lesions where they accumulate a large amount of lipids, which promotes their differentiation into foam cells. Meanwhile, M1 macrophages secrete tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and metalloproteinases, which exacerbate and destabilize lesion development. However, M2 macrophages predominate in the early stages of atherosclerosis and are characterized by IL-10 secretion and smaller amounts of accumulated lipids; these events are atheroprotective and can reduce plaque development [49].

DC precursors or monocytes are recruited to lesions where they differentiate into DCs. The DC population is heterogeneous and can be divided into four major categories: conventional DCs (cDCs), plasmacytoid DCs (pDCs), monocyte-derived DCs, and Langerhans cells [50]. DC accumulation in regions prone to AD suggests that their recruitment accounts for an initial inflammatory or immune activation. The exact localization and origin of vascular DCs, however, is still under debate [51]. In general, immature and semimature DCs uptake lipids and other intimal antigens, thus preventing them from eliciting pro-inflammatory signaling in other artery wall cells. Toll-like receptor (TLR) ligation by ligands such as oxLDL induces DC maturation. Under hyperlipidemic conditions, lipid uptake and efferocytosis likely lead to DC-foam cell formation, and mature DCs and foam cells emigrate from the vessel wall in a C-C chemokine receptor type 7 (CCR7)-dependent manner, clearing inflammatory cells, lipids, and apoptotic cell debris from the intimal space and preventing necrosis and persistent inflammation. Mature CD11b+ DCs likely expand regulatory T cells (Tregs) and CD4+ effector T cells within the artery wall [52]. CD4⁺CD25⁺Foxp3⁺ Tregs can protect the pro-inflammatory activation of vascular cells. The mechanisms by which Tregs protect against inflammation are thought to be mediated, at least in part, by directing cell-to-cell interactions as well as through the secretion of soluble anti-inflammatory cytokines, including IL-10 TGF-β [53]. Thus, further studies are required to understand the role of adaptive immunity and inflammation response in AD with CRS.

The role of increased SNS activity in IR with CRS is increasingly recognized. Individuals with central obesity show increased sympathetic nervous activity. Increased sympathetic outflow has been reported in obese nonhypertensive individuals with the determination of circulating catecholamines, urinary norepinephrine (NE), and muscle sympathetic nerve activity (MSNA) [54]. Multiple neurohumoral mechanisms can activate the SNS in patients with CRS including direct activation of the SNS in response to the activation of higher cerebral nuclei and renal afferent nerve activation mediated by perirenal fat accumulation and kidney compression [55]. Sympathetic activation can also be triggered by reflex mechanisms such as arterial baroreceptor impairment, psychological stress, oxidative stress, obstructive sleep apnea, inflammation, and metabolic factors and dysregulated production and secretion of adipokines from visceral fat with a particular important role of leptin [20]. Although enhanced activation of SNS is an important component in IR, it is often related to activation of RAAS since the RAAS system causes sustained sympathetic overactivity by modulating central neurons in the subfornical organ of the forebrain [49]. The link between sympathetic nervous activity and AD offers new clues to identify AD and may allow for development of novel-targeted therapeutic interventions.

There is evidence that RAAS activation plays an important role in the pathogenesis of AD. In the course of RAAS-induced vascular injury, Ang II binds to its type 1 receptor to induce oxidative stress, mainly mediated by NADPH oxidase. Our study has also found that Ang II increased serine phosphorylation of IRS-1 and inhibited the insulin-stimulated phosphorylation of endothelial NO synthase through activation of S6 kinase (S6K) signaling pathway [30]. Recent data also suggests that increased mineralocorticoid receptor (MR) is associated with IR. Studies have demonstrated a relationship between MR activation and decreased insulin sensitivity in animal models and humans. For example, patients with primary hyperaldosteronism were found to have IR suggesting the contribution of MR signaling to IR [56]. Spironolactone, a blocker of the MR, has been shown to decrease local inflammation and vascular stiffness in rodent models of hypertension and IR [57, 58]. These observations suggest that inhibition of MR might be a beneficial therapeutic approach for preventing AD in diet-induced obesity and IR [58]. Thus, enhanced RAAS activation may represent a link between obesity, hypertension, dyslipidemia, and IR, features present in the AD with CRS [59]. Moreover, cross-talk between Ang II and aldosterone signaling underscores the importance of Ang II–aldosterone interactions in the development of IR, vascular dysfunction, and AD.