Perivascular Adipose Tissue as a Relevant Fat Depot for Cardiovascular Risk in Obesity

Abstract

Obesity is associated with increased risk of premature death, morbidity, and mortality from several cardiovascular diseases (CVDs), including stroke, coronary heart disease (CHD), myocardial infarction, and congestive heart failure. However, this is not a straightforward relationship. Although several studies have substantiated that obesity confers an independent and additive risk of all-cause and cardiovascular death, there is significant variability in these associations, with some lean individuals developing diseases and others remaining healthy despite severe obesity, the so-called metabolically healthy obese. Part of this variability has been attributed to the heterogeneity in both the distribution of body fat and the intrinsic properties of adipose tissue depots, including developmental origin, adipogenic and proliferative capacity, glucose and lipid metabolism, hormonal control, thermogenic ability, and vascularization. In obesity, these depot-specific differences translate into specific fat distribution patterns, which are closely associated with differential cardiometabolic risks. The adventitial fat layer, also known as perivascular adipose tissue (PVAT), is of major importance. Similar to the visceral adipose tissue, PVAT has a pathophysiological role in CVDs. PVAT influences vascular homeostasis by releasing numerous vasoactive factors, cytokines, and adipokines, which can readily target the underlying smooth muscle cell layers, regulating the vascular tone, distribution of blood flow, as well as angiogenesis, inflammatory processes, and redox status. In this review, we summarize the current knowledge and discuss the role of PVAT within the scope of adipose tissue as a major contributing factor to obesity-associated cardiovascular risk. Relevant clinical studies documenting the relationship between PVAT dysfunction and CVD with a focus on potential mechanisms by which PVAT contributes to obesity-related CVDs are pointed out.

Keywords: adipokine; cardiovascular risk; obesity; perivascular adipose tissue; vascular function.

Figure 1

Mechanisms by which systemic adipose tissue dysfunction could lead to the development of vascular dysfunction in obesity. Adipose tissue produces various chemokines, cytokines and hormones, which are secreted into the circulatory system and act in several physiological processes, including energy balance, immune responses, blood pressure, vascular homeostasis and angiogenesis, glucose and lipid metabolism. Expansion of the adipose tissue leads to necrotic and/or apoptotic cell death and this is paralleled by infiltration of activated macrophages, increased production of pro-inflammatory adipokines and reactive oxygen species, promoting a state of systemic endothelial cell activation and vascular dysfunction, all of which may contribute to the elevated cardiovascular risk associated with obesity.

Figure 2

Perivascular adipose tissue dysfunction and obesity-associated vascular dysfunction. Perivascular adipose tissue (PVAT) secretes a wide variety of biologically active molecules, including the adipokines, which modulate vascular tone, smooth muscle cells migration and proliferation, neointimal hyperplasia, inflammatory responses, and oxidative stress. Obesity is associated with structural and functional changes in PVAT, leading to an imbalance in favor of vasoconstrictor and pro-inflammatory substances, adipocytes hypertrophy as well as changes in insulin signaling pathways. SMC, smooth muscle cell; ROS, reactive oxygen species; NO, nitric oxide.