Microvascular function

Obesity is a significant component of the metabolic syndrome and contributes to increased cardiovascular risk through dysregulation of vascular function [1]. The inflammatory pathways associated with obesity act through cellular mechanisms to modify vascular endothelial and smooth muscle function, causing a cascade of structural and functional adaptive processes in both large capacitive vessels and resistive vessels of small calibre in the microcirculation [1,2]. The vasoactivity of the microcirculatory beds regulates blood flow for adequate tissue perfusion. It also contributes to resistive changes that affect peripheral wave reflection, thus influencing haemodynamic relationships between arterial pressure and flow, and affecting ventricular load [3]. The interplay between the large conduit vessels and microcirculation is considered a common factor in the disease spectrum of the metabolic syndrome and has been proposed as a potential mechanistic target for pharmacological intervention for significant cardiovascular risk factors [4,5]. The processes that predominantly affect cell signalling in blood vessels are generally considered to be mediated by direct activity of compounds transported in the blood stream, the effects of mechanical forces due to distending pressure or blood flow or by direct neurogenic effects. In the peripheral vasculature, the overall effect is to modulate smooth muscle tone in the precapillary vessels so as to alter vessel calibre and so resistance of the peripheral vascular beds. Both large and small vessels are generally tethered to the surrounding tissue, with the peripheral vessels in the microcirculation having an abundance of perivascular adipose tissue (PVAT). As in the case of vascular endothelial cells, which were once thought to provide simply a passive physical interface for the flowing blood, but now considered to be a highly important regulatory constituent of the circulatory system, evidence has been emerging to suggest a highly active role for PVAT [6]. Under normal conditions, PVAT produces substances that diffuse from the external environment of the vessel to act on the vascular smooth muscle cells to reduce the contractile response. That is, it provides a counterbalance to the predominantly vasoconstrictor influences, occurring through the vasorelaxant effects of adipokines [7]. With increase in inflammation and associated oxidative stress, as occurs in obesity, the bioavailability of adipokines is reduced and so is the vasorelaxant effect, which is considered to be a ‘protective effect’ [8]. A large body of work on the active metabolic properties of PVAT has elucidated the role of local effects of components of the renin–angiotensin–aldosterone system (RAAS). The local effects of angiotensin mediated by inflammation, the localization of angiotensin type 1 and type 2 receptors to adipocytes [9] and the expression of the minerolocorticoid receptor on adipose tissue [10], for which aldosterone is the primary ligand, suggest a potentially explicit role of the RAAS in relation to the effects of PVAT on the functional behaviour of vessels in the peripheral microcirculation [11,12]. In this issue of the Journal, the study by Agabiti-Rosei et al.[13] addresses the effects of PVAT on the contractile properties of vessels of the microcirculation. The study involves measurement of contraction of rat mesenteric vessels using wire myography. Measurements were made in vessels with and without PVAT and with PVAT in the presence of an angiotensin-converting enzyme (ACE) inhibitor (captopril) and an angiotensin receptor blocker (ARB, telmisartan). The authors used the established manoeuvre of hypoxia to simulate the blunted vasorelaxant (or anti-contractile) effect seen with PVAT under inflammatory conditions, as occurs in obesity [8]. The experiments are elegant. The findings confirm that the presence of PVAT in mesenteric vessels of the order of 200–300 μm diameter causes reduced contraction in response to norepinephrine when compared to vessels in the absence of PVAT. The effect is essentially abolished in vessels with PVAT subjected to hypoxia. In this situation, the ‘protective’ anti-contractile effect which was lost with hypoxia can be rescued equally by both ACE inhibition and ARB. The finding that no significant difference was observed with captopril or telmisartan is suggestive of the effect being due to the activity of local angiotensin associated with adipocytes. The findings of the study by Agabiti-Rosei et al.[13] are significant insofar as they address a stimulus of vascular control which is external to the vascular blood stream; the role of adipose tissue potentially modulating vascular blood flow through geometrical changes of resistance vessels. The study also provides a first demonstration of the involvement of the RAAS on the effects of PVAT on microvascular function, and that the inflammation-induced loss of the vasorelaxant effect, as occurs in obesity, can be recovered by agents that interrogate the RAAS. This study has demonstrated the effects of local angiotensin. The effects of aldosterone can also be inferred from previous studies [14], including those assessing the role of mineralocorticoid receptor blockade on resistance arteries [15,16] as well as conduit vessels [17]. The results of the study by Agabiti-Rosei et al.[13] rely uniquely on the use of the established technique of wire myography [18]. A potentially critical observation using this technique to measure contractility with and without PVAT is that the physical mass of adipose tissue attached to the vessel could confound the measurement of force or displacement of the vessel wall due to smooth muscle tone. Although this issue is not explicitly addressed by the authors, they highlight the fact that other studies addressing the wall properties of resistance vessels do not show differences between normal, obese and hypertensive patients [19,20]. The assumption is that this can also be extended to animal models of obesity. However, in the study by Agabiti-Rosei et al.[13], the model of obesity constituted simply the use of hypoxia to simulate the obesity-induced inflammatory condition on the loss of the anti-contractile effects of PVAT. Notwithstanding the possibility of the adipose tissue surrounding the vessel affecting the actual measurements of the vessel contractile response, the differences between the effects of hypoxia and the effects of the ACE inhibitor and the ARB on the contractile response in the presence of PVAT are quite large (changes of two to four-fold). This would suggest that the surrounding mass of adipose tissue would have minimal effect on wall properties in confounding the contractile force due to smooth muscle tone being influenced by external stimuli. The experimental hypoxia stimulus used in the study by Agabiti-Rosei et al.[13] has uncovered potential additional mechanistic information regarding the interaction of the RAAS and local inflammatory processes. Exposure of adipose tissue to hypoxia results in up-regulation of the hypoxia-sensitive transcription factor (HIF-1α), reduction in adiponectin levels in adipocytes and increase in pro-inflammatory adipokines [21]. HIF-1α has been shown to be associated with up-regulation of ACE protein expression and so leading to formation of angiotensin II (Ang II) [22]. This activation of the RAAS suggests the possible direct contribution of HIF-1α to the inflammatory process and so the alteration of the PVAT activity to lose the anti-contractile effect. This therefore suggests the intriguing possibility of a positive feedback mechanism, in which the loss of the ‘protective’ anti-contractile vascular effect by the PVAT is further amplified by the hypoxic stimulus via the activity of HIF-1α associated with production of Ang II. The possibility that interrogation of the RAAS can restore the loss of the anti-contractile effect of PVAT on vascular function due to inflammation and oxidative stress present in obesity opens up avenues for affecting the overall interplay between the large and small vessels [4,5]. In mouse models of diet-induced obesity, it was found that arterial stiffness precedes the development of hypertension [23]. Thus, the ability to modulate or to reduce the gain of the positive feedback mechanism associated with PVAT and HIF-1α through blockade of the RASS components presents an additional means of controlling the peripheral vasculature so as to reduce wave reflection, and so reduce pulse pressure in the presence of increased arterial stiffness. In addition to the elucidation of mechanisms of control of microvascular function, and so of tissue perfusion, by active metabolic factors related to adipose tissue, these findings also suggest possible applications to other specific conditions associated with obesity and hypoxia, presenting increased cardiovascular risk, such as obstructive sleep apnoea. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.