The pathobiology of perivascular adipose tissue (PVAT), the fourth layer of the blood vessel wall.

The perivascular adipose tissue (PVAT) is an adipose tissue depot which surrounds most human blood vessels. It is metabolically active and has both a protective and a pathogenic role in vascular biology and pathobiology. It regulates vascular homeostasis and promotes vascular dysfunction. The purpose of this review is to consider the origin, structure, function, and dysfunction of this unique adipose depot consisting of white (WAT), brown (BAT) and beige adipose tissue, to support the concept that PVAT may be considered the fourth layer of the normal arterial wall (tunica adiposa), in which dysfunction creates a microenvironment that regulates, in part, the initiation and growth of the fibro-inflammatory lipid atherosclerotic plaque. Experimental in-vivo and in-vitro studies and human investigations show that the adipocytes, extracellular matrix, nerve fibers and vasa vasorum found in PVAT form a functional adipose tissue unit adjacent to, but not anatomically separated from, the adventitia. PVAT maintains and regulates the structure and function of the normal arterial wall through autocrine and paracrine mechanisms, that include modulation of medial smooth muscle cell contractility and secretion of anti-inflammatory molecules. PVAT shows regional phenotypic heterogeneity which may be important in its effect on the wall of specific sections of the aorta and its muscular branches during perturbations and various injuries including obesity and diabetes. In atherosclerosis, a pan-vascular microenvironment is created that functionally links the intima-medial atherosclerotic plaque to the adventitia and PVAT beneath the plaque, highlighting the local impact of PVAT on atherogenesis. PVAT adipocytes have inflammatory effects which in response to injury show activation and phenotypic changes, some of which are considered to have direct and indirect effects on the intima and media during the initiation, growth, and development of complicated atherosclerotic plaques. Thus, it is important to maintain the integrity of the full vascular microenvironment so that design of experimental and human studies include investigation of PVAT. The era of discarding PVAT tissue in both experimental and human research and clinical vascular studies should end.