AT is the body's largest endocrine organ and secretes hormones, cytokines, and proteins in endocrine and/or paracrine manners that affect cell and tissue function throughout the body (5). AT is also essential in maintaining lipid and glucose homeostasis, which becomes dysfunctional in obesity and excessive deposition of fat occurs. Enlarged adipocytes in obese individuals promoted macrophage-mediated inflammation and adipokine-induced insulin resistance (6). The pathological function of AT is determined by their cellular composition, secretome (secretion profiles), and location in the human body (7). Further, low storage and removal of adipose triglycerides promote dyslipidemia, while high storage and low removal prompt obesity (8). In addition, detection of brown and/or beige AT in adult humans (9, 10) and the realization of adipocyte heterogeneity and plasticity of white AT spurred great interest in targeting AT for possible therapeutic advantages (11).

Impairment of flow-induced vasodilation, arterial dilation prompted by blood flow, is one hallmark of obesity-induced ED. It is demonstrated by the impairment of endothelial nitric oxide synthase (eNOS) and the loss of nitric oxide (NO), a major vasodilator and anti-inflammatory agent (12). Obesity also promotes damage of the endothelial glycocalyx, which responds to mechanical force from blood vessels and regulates NO production. Flow-mediated vasodilation in mouse and human mesenteric arteries was hindered by loss of the endothelial flow-sensitivity of Kir (inwardly rectifying K⁺) channel due to obesity-induced glycocalyx thinning (13). Defective physiological properties of endothelial cells (EC) will switch the vascular endothelium to a pro-inflammatory, prothrombotic and proatherogenic phenotype, leading to leukocyte adhesion, activation of platelets, and pro-oxidation of mitogens, along with impaired endothelial NO production, decreased synthesis of endothelium-derived hyperpolarizing factors (EDHF), and increased vasoconstriction factors, such as angiotensin II (Ang II) and prostaglandin (PGH2) (14). Through activation of adhesion molecules, leukocyte proliferation, and transmigration, ED reportedly launches CVD progression in obesity (15). Moreover, secretion of angiotensinogen of the renin-angiotensin system (RAS) by dysfunctional adipocytes leads to its overexpression in RAS, enhancing ROS production and increasing the atherogenic and thromboembolic potentials of EC (16). The risks associated with cardiovascular complications can be mitigated through inhibition of inflammatory mechanisms and controlling obesity (16).

Associated with connective tissue and blood vessel proliferation, inflammation has been regarded as the first stage of vascular dysfunction. AT-derived tumor necrotic factor-α (TNF-α) is one product of inflammation (18). In obesity, microvasculature from VAT is an important source of low-grade inflammation and oxidative stress. Both contribute to vascular changes and favor increased atherosclerosis under clinical conditions. Mechanistically, excessive macronutrients accumulated on the AT promote the secretion and release of inflammatory mediators, including interleukin-6 (IL-6), interleukin-1β (IL-1β), TNF-α, leptin, and stimulation of monocyte chemoattractant protein-1 (MCP-1), which subsequently produce less adiponectin, thereby initiating a proinflammatory state (16) and driving vascular destabilization and leakage (19).

Among AT-secreted factors, MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that play important roles in a variety of cellular processes, such as differentiation, proliferation, apoptosis, and stress response; their alteration contributes to the development of many pathologies, including obesity (20). Specifically, AT-derived miRNA (21) mediates obesity-induced ED by affecting gene expression of eNOS, SIRT1, cellular producers of ROS, autophagy machinery, and ER stress (22).

PVAT and EAT elicit direct impacts on the adjacent vascular wall or myocardium, respectively, through the paracrine release of bioactive mediators. These mediators travel to neighboring vessels, thereby regulating the biology of entire vascular beds in a “vasocrine” manner (23). In obesity, PVAT-secreted high-concentrations of adipokines (e.g., TNF-α and IL-6) access the vascular lumen and suppress the PI3-K pathway of insulin signaling, which unlocks the vasoconstrictor effects of endothelin 1, leading to a reduction in insulin-mediated muscle nutritive blood flow, contributing to insulin resistance (23). PVAT also releases miRNA, including miR-221-3p, which is highly enriched in obese PVAT and recently reported to induce ED by vascular remodeling (24). EAT has close proximity to the adventitia of the coronary arteries and shares the same microcirculation as the underlying myocardium (25, 26). When adversely remodeled and dysfunctional in obesity, EAT secretes proinflammatory cytokines, contributing directly to the pathogenesis of coronary artery disease (27).

Targeting peripheral vascular EC to improve ED has been long exploited (29). Recent studies showed that heterozygous eNOS deficiency was associated with ED in diet-induced obesity (55). Patients with abnormal arginine metabolism and bioavailability due to obesity displayed lower cardiometabolic risk after treatment with a slow-release eNOS substrate, arginine (30). Vascular function could be rescued in obese vessels by targeting EC-Ca²⁺ toolkit, although this was not tested in obese subjects (56). A recent study showed that deletion of fat mass and obesity-associated protein (FTO) in EC rescued metabolic and vascular function in obesity (33), independent of its known function in regulation of obesity (57). Vascular arginase reduces NO bioavailability, which hastens microvascular remodeling in obesity (31). EC-derived arginase mediates obesity-induced vascular dysfunction and arterial stiffening (32), implicating arginase as a potential target of obesity-induced ED.

Oxidative stress is a key pathogenic factor of microvascular complications in metabolic disease. Renal Nox1, Nox2, and Nox4 contribute differentially to vascular oxidative stress-associated ED in obesity, suggesting a need to identify specific Nox subunits as a target (34), which may result in effective prevention of obesity-related CVD (35). Oxidative stress-associated inflammation is another frequently tested target. CD40 ligand (CD40L) signaling regulates ED via immune cell recruitment and platelet activation in mouse models of hypertension, the mechanism of which extended to mouse models of obesity, implicating CD40L as a therapeutic target for lipid dysmetabolism (36). Neutrophil extracellular traps (NETs) have an inflammatory web-like chromatin structure (37). Inhibition or degradation of NETs prevented ED in mouse model of obesity (38) Further, adipose macrophage infiltration enhanced vascular ED in obese subjects (58). Blocking infiltration of macrophages and T lymphocytes in PVAT prevented obesity-induced ED in mice with G protein-coupled receptor kinase 2 (GRK2) deletion in myeloid cells (42), suggesting GRK2 as a potential therapeutic target. Deletion of lipoxin receptor in leukocytes led to unsolved inflammation in mice, which augmented ED with diabetic cardiomyopathy in obesity (59). Similar therapeutic potentials have been found in other inflammatory mediators, such as adipokine and leptin (43).

Obesity is a strong predictor of hypertension, although it remains unknown how obesity increases blood pressure (60). ED is a hallmark of obesity-induced hypertension. Insulin resistance and increased systolic blood pressure led to ED in obesity; however, targeting these factors presented with different benefits depending on sex (61) and ethnic group (62). RAS hyperactivity was often thought to result from Ang II-dependent stimulation of the Ang II type 1 receptor (AT1R). Recently, the soluble (pro)renin receptor was found to induce ED and hypertension by activating AT1R in high-fat diet (HFD) feeding mice (41). Another recent study reported that endothelial transient receptor potential vanilloid 4 channels (TRPV4) was impaired in a mouse model of diet-induced obesity and obese human resistance vessels, resulting in increased blood pressure (39). This contrasted with findings from another recent study in the same mouse model, but with a longer duration on HFD feeding, which implicated Ca²⁺-spark vasoregulation as the underlying mechanism (40). Prolonged HFD feeding in mice appeared to improve the vascular response to leptin, which overrode ED induction (63) In any case, strategies to preserve or protect a functional target on EC would bear promise to improve ED and hypertension in obesity.

In terms of safety, cost, and effectiveness, most clinical approaches targeting AT have not been successful in the treatment of AT-induced CVD (28). However, some commonly used anti-hyperglycemic medications and lifestyle intervention could elicit a dual action: improving AT function and conferring an appreciable cardiovascular benefit.

Glucagon-like peptide 1 (GLP1) is an incretin, responsible for insulin secretion, glucagon inhibition, and decreased gastrointestinal motility in the post-prandial setting. GLP1 is inactivated by dipeptidyl peptidase 4 (DPP4), an AT-expressing enzyme. GLP1 agonists (e.g., liraglutide) and DPP4 inhibitors (e.g., sitagliptin) are now being used in the management of type 2 diabetes mellitus with improved cardiovascular outcomes in clinical trials (44, 45), implicating AT involvement (46). Sodium–glucose transporter 2 (SGLT2) (e.g., empagliflozin) is responsible for renal glucose reabsorption, the inhibition of which also exerted direct AT effects with a cardioprotective profile (47). As reported in a meta-analysis, SGLT2 inhibitors generated consistent beneficial outcomes for heart failure and kidney disease, with certain heterogeneity in cardiovascular deaths (48). Whether endothelial function and/or inflammatory response are improved and whether they are associated with the favorable outcomes in these trials remain to be determined.

Since positive cardiovascular outcomes have been observed in patients with established CVD by the use of anti-inflammatory agents [e.g., canakinumab (64)], interfering with AT inflammation could generate favorable outcomes. Indeed, in rodent models of obesity, several pharmaceuticals [e.g., metformin (49), resveratrol (50), and methotrexate (51)] are reported to reduce pro-inflammatory cytokine expression in AT and promote adiponectin expression, thereby rescuing eNOS phosphorylation and endothelial function.

Lifestyle intervention (e.g., exercise and diet) is one of the best approaches, especially when medicines are not available or existing medicines have failed. ED directly impairs basic vascular function (e.g., blood flow alteration), which made it a great target for pharmacological and/or exercise intervention with insulin-based therapies (57). Obese individuals who performed an acute high-intensity interval exercise presented with improved plasma pentraxin 3 and endothelial function (52). Even a short-term weight loss could reverse obesity-induced microvascular ED (53). Calorie restriction improved vascular insulin sensitivity, which was associated with downregulation of pro-inflammatory cytokine production in aged AT (54).

Given the functional AT-EC interaction, targeting both AT and EC (“dual-action therapies”) would be a better approach for obesity (65–67), which might lead to the cardiovascular benefits observed in different large-scale clinical trials (68).