Human Perivascular Adipose Tissue as a Regulator of the Vascular Microenvironment and Diseases of the Coronary Artery and Aorta

Abstract

Perivascular adipose tissue (PVAT) is an adipose depot that surrounds blood vessels in the human body and exerts local paracrine signaling. Under physiologically healthy conditions, PVAT has an anti-contractile effect on vessels, but in obesity this effect is lost. During metabolic disease, adiponectin secretion is dysregulated, influencing nitric oxide bioavailability and macrophage infiltration and inflammation, all of which mediate PVAT signaling. However, based on the location in the body, and the type of adipocyte present, PVAT has different relationships with risk factors for disease. Imaging studies in patients with cardiovascular disease have demonstrated important associations between PVAT structure and pathology, yet insight into molecular pathways regulating human PVAT function are still lacking. This review focuses on our current understanding of human PVAT and its secretory role in the vascular microenvironment. A current area of priority is defining molecular differences in the secretome between PVAT depots, as this could inform the treatment of diseases that occur in anatomically restricted locations. In addition, understanding progressive changes in PVAT structure and function during metabolic disease is required for effective targeted therapies.

Keywords: Cardiovascular disease; Paracrine; Perivascular adipose tissue; Secretome; Signaling.

Figure 1.. PVAT Influence On Human CVD.

Characteristics of PVAT are distinct based on anatomical location. In humans, PVAT surrounding coronary arteries, thoracic aorta, and abdominal aorta have been studied. The volume of PVAT has been positively correlated to cardiovascular disease risk, with increasing PVAT volume surrounding the thoracic aorta associated with increased metabolic risk factors. Thus, clinical imaging techniques may be useful for diagnostics or monitoring. Signaling mechanisms by which human PVAT influences disease include modification of vasoregulatory pathways such as nitric oxide, adipokines, and reactive oxygen species (ROS). Although more studies are analyzing these pathways in patients and human tissues, most of our molecular signaling information has been derived from pre-clinical studies, particularly using mouse models. Those results have informed the following model of how alterations in PVAT in obesity may promote vascular disease: as PVAT volume increases and becomes more lipid-storing, there is decreased adiponectin and nitric oxide production, leading to increased vasoconstriction and generation of reactive oxygen species. Inflammation within PVAT is also associated with obesity and metabolic disease, and we predict that activation of inflammatory cytokines contributes to a feed-forward pathological loop. Our studies in PVAT suggest that the well-known trafficking and secretory molecule, Rab27a, may contribute to these processes by activation during obesity to change the content and/or rate of secretion of paracrine factors derived from adipocyte progenitors, mature adipocytes, or inflammatory cells within PVAT. This mechanism is currently under investigation. PVAT dysfunction has implications for coronary artery disease, arterial calcification, abdominal aortic aneurysm (AAA), and peripheral artery disease in humans.