Anticontractile Effect of Perivascular Adipose Tissue and Leptin are Reduced in Hypertension.

Leptin causes vasodilatation both by endothelium-dependent and -independent mechanisms. Leptin is synthesized by perivascular adipose tissue (PVAT). The hypothesis of this study is that a decrease of leptin production in PVAT of spontaneously hypertensive rats (SHR) might contribute to a diminished paracrine anticontractile effect of the hormone. We have determined in aorta from Wistar-Kyoto (WKY) and SHR (i) leptin mRNA and protein levels in PVAT, (ii) the effect of leptin and PVAT on contractile responses, and (iii) leptin-induced relaxation and nitric oxide (NO) production. Leptin mRNA and protein expression were significantly lower in PVAT from SHR. Concentration-response curves to angiotensin II were significantly blunted in presence of PVAT as well as by exogenous leptin (10(-9) M) only in WKY. This anticontractile effect was endothelium-dependent. Vasodilatation induced by leptin was smaller in SHR than in WKY, and was also endothelium-dependent. Moreover, release of endothelial NO in response to acute leptin was higher in WKY compared to SHR, but completely abolished in the absence of endothelium. In conclusion, the reduced anticontractile effect of PVAT in SHR might be attributed to a reduced PVAT-derived leptin and to an abrogated effect of leptin on endothelial NO release probably due to an impaired activation of endothelial NO synthase.

Papel del tejido adiposo perivascular en la función vascular / Role of perivascular adipose tissue on vascular function

En los últimos años se ha puesto de manifiesto el papel del tejido adiposo perivascular (TAPV) en la regulación del tono vascular. Soltis y Cassis fueron los primeros investigadores en demostrar que la presencia de TAPV reducía de forma significativa las contracciones de la aorta de rata a noradrenalina. Recientemente, se ha confirmado el efecto anticontráctil de este tejido en presencia de una gran variedad de vasoconstrictores, tanto en aorta y arteria mesentérica de rata, como en arterias humanas. La causa de este efecto es el factor relajante derivado de adipocitos, de estructura desconocida. Su efecto anticontráctil parece estar mediado por diferentes mecanismos en función del lecho vascular y la especie estudiados. Además, el TAPV es fuente de leptina, que también modula el tono vascular mediante 2 mecanismos diferentes: a) una vasoconstricción indirecta a través de la estimulación simpática en el ámbito hipotalámico, y b) una vasodilatación directa a través de un endotelio funcional. Por otra parte, el TAPV también libera factores vasoconstrictores. Expresa todos los componentes del sistema renina-angiotensina y produce angiotensina II. También libera otros factores con efectos vasoactivos, como el anión superóxido y diversas citocinas inflamatorias. Se ha demostrado que cambios en la cantidad de TAPV, en situaciones como hipertensión y obesidad, están asociados con un desequilibrio entre la producción de vasodilatadores y vasoconstrictores y con alteraciones en la función vascular (AU)

In the last years a paracrine role for perivascular adipose tissue (PVAT) in the regulation of vascular function has been uncovered by several studies. Soltis and Cassis were the first to demonstrate that PVAT significantly attenuates vascular responsiveness of rat aortic rings to norepinephrine. More recent reports have confirmed the inhibitory action of PVAT on the contractile response to a variety of vasoconstrictors on rat aortic and mesenteric arteries, as well as on human thoracic arteries. The anti-contractile action is induced by a still undefined transferable factor released by periadventitial fat, called adipocyte-derived relaxing factor. Its anticontractile effect seems to be mediated by different mechanisms depending on the type of vascular bed and species. In addition, PVAT is a source of leptin, which participates in the regulation of vascular tone. Vascular effects of leptin are the net result of two different actions: a) indirect vasoconstriction through stimulation of sympathetic activity at hypothalamic level, and b) direct vasodilatation that depends on intact and functional endothelium through mechanisms that vary between different vascular beds. Moreover, PVAT also releases several vasoconstrictors. It expresses the components of the renin-angiotensin system and releases angiotensin II. Other factors with vasoactive effects, such as superoxide anion and inflammatory cytokines, have also been described. Changes in the amount of PVAT in different situations such as hypertension and obesity are related to an altered balance of vasoconstrictors and vasodilators, thus contributing to changes in arterial blood pressure (AU)

A reduction in the amount and anti-contractile effect of periadventitial mesenteric adipose tissue precedes hypertension development in spontaneously hypertensive rats.

The aim of this study was to determine whether alterations in periadventitial adipose tissue and its anti-contractile effect precede hypertension development. We used 4-week-old male Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), which were pre-hypertensive. Vascular function was studied in the perfused mesenteric bed (MB, 1.5 mL/min). MB weight was lower in SHR (8.0 +/- 0.3 mg/g body weight) than in WKY (9.0 +/- 0.3 mg/g body weight) rats. Concentration-response curves to KCI (6 to 75 mmol/L) and to acetylcholine (10(-9) to 10(-5) mol/L) were similar between groups. Contractile responses to serotonin (10(-9) to 10(-5) mol/L) were significantly higher in SHR compared to WKY. 4-Aminopyridine (4-AP, 2 mmol/L), a blocker of Kv channels, induced a similar increase in perfusion pressure in both strains. However, 4-AP (2 mmol/L) significantly increased the contractile response to serotonin (10(-9) to 10(-5) mol/L) only in WKY. The anti-contractile effect of fat was confirmed by a comparison of (+) fat and (-) fat mesenteric arteries, which revealed that 4-AP significantly enhanced contractions only in (+) fat rings from WKY. These results show that alterations in visceral periadventitial fat mass and function in SHR precede hypertension, suggesting a constitutive mechanism independent of age and the hypertensive state.