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The Importance of Perivascular Adipocytes. By Dr Craig Daly, University of Glasgow

In the last few years there has been a steadily increasing interest in the possible importance of perivascular fat. Like the endothelium (pre 1980’s), the perivascular adipocytes were previously thought to be unimportant and were discarded prior to investigation of the physiology and pharmacology of isolated vascular segments. With the benefit of hindsight, that might have been a bad idea. This short commentary provides a quick introduction to the possible importance of perivascular adipocytes.

Vessel structure: The blood vessel wall is comprised of three main tunics separated by two elastic sheets. The inner layer of cells, the tunica intima, comprises a single layer of endothelial cells which are in contact with blood on their luminal surface and are attached to the internal elastic lamina (IEL) on their abluminal surface. The IEL has holes (fenestrae) which permit the formation of myo-endothelial connections between the endothelial cells and smooth muscle cells of the tunica media. The medial smooth muscle is separated from the tunica adventitia by the external elastic lamina (EEL). The EEL is a loose weave of elastin and so there is ample opportunity for adventitial cells to make contact with the medial smooth muscle. However, such connections are not widely recognised. In fact the overall structure and function of the vascular adventitia is poorly understood and has only recently attracted the attention of investigators. Virtually nothing is known about the adipocytes that surround the blood vessels, although recent reports have indicated an extremely important modulatory role in vascular reactivity and general vascular health.

Obesity: A report published by the Association of Public Health Observatories identified the UK as having the highest levels of obesity in Europe. The increased risk of hypertension and diabetes, among the obese population, has been comprehensively reviewed and reported on in the popular press. The main focus of these reports has tended to be on visceral fat and body mass index (BMI). The fact that obese elderly people are rarely seen perhaps speak volumes. What has been overlooked is the, possibly devastating, direct effect that fat may have on the normal functions of the vasculature.

Adipokines: Body fat (adipocytes) can now be regarded as an important part of the endocrine system and may even represent an endocrine organ in itself. Numerous factors (adipokines) are released from adipocytes and these can be either anti-atherogenic or pro-atherogenic. The list of adipokines includes, but is not limited to; tumor necrosis factor (TNF-α), adiponectin, plasminogen activator inhibitor-1 (PAI-1), resistin, Heparin-binding epidermal-growth-factor-like growth factor (HBEGF), interleukin 1 (IL-1) and leptin. Two particularly important adipokines related to obesity and cardiovascular disease are adiponectin (anti-atherogenic) and IL-1 (pro-atherogenic). Unfortunately in cases of obesity, levels of the protective adiponectin are reduced whilst those of IL-1 are increased.

Vascular adipocytes: In addition to the wide array of adipokines, the vascular adipocytes also express a host of receptors including; alpha1a- & alpha1b-adrenoceptors, beta1- & beta3-adrenoceptors, P1, P2x & P2y purinoceptors, cannabinoid receptors (GPR55, CB1 & CB2), substance-p (NK1). Therefore, the circumstantial evidence suggests a possible interaction between the sympathetic neurotransmitters noradrenalin and ATP, the sensory transmitter Substance-P and the endocannabinoids. A picture is now emerging that supports a model of adventitial nerves activating perivascular adipocytes which then release factors that have direct effects on all vascular cell types.

Vascular modulation: Simple experiments in which the perivascular fat is removed from segments of blood vessels prior to in-vitro experimentation are providing surprising results. In most cases the responses to the catecholamines, noradrenalin and adrenalin, are inhibited when fat is present. Therefore, published reports may have overestimated the physiological role of these catecholamines since most in-vitro experiments are performed following ‘careful removal of perivascular fat’. One surprising observation is that the responses to some agonists are actually increased in the presence of fat thus demonstrating that the presence of fat per se does not just simply block access of the exogenously applied drugs.

So, when we are performing experiments on isolated vascular segments should we keep the fat on or remove it? We generally ask the same question of the endothelium and adjust our experiments accordingly. I believe we have now reached a point where we must treat the perivascular fat with the same degree of respect that is given to the endothelium. Most of the work that has been published on perivascular fat has been on experimental animals. Given that obesity and cardiovascular disease are seriously debilitating (and costly) human disorders it will be interesting to examine a range of arteries and veins taken from patient biopsies.

Overall, the study of perivascular fat could hold the key to new cardiovascular therapies.

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