Role of Perivascular Adipose Tissue–Derived Methyl Palmitate in Vascular Tone Regulation and Pathogenesis of Hypertension

Abstract

Background-Perivascular adipose tissue (PVAT)-derived relaxing factor (PVATRF) significantly regulates vascular tone. Its chemical nature remains unknown. We determined whether palmitic acid methyl ester (PAME) was the PVATRF and whether its release and/or vasorelaxing activity decreased in hypertension. Methods and Results-Using superfusion bioassay cascade technique, tissue bath myography, and gas chromatography/mass spectrometry, we determined PVATRF and PAME release from aortic PVAT preparations of Wistar Kyoto rats and spontaneously hypertensive rats. The PVAT of Wistar Kyoto rats spontaneously and calcium dependently released PVATRF and PAME. Both induced aortic vasorelaxations, which were inhibited by 4-aminopyridine (2 mmol/L) and tetraethylammonium 5 and 10 mmol/L but were not affected by tetraethylammonium 1 or 3 mmol/L, glibenclamide (3 mol/L), or iberiotoxin (100 nmol/L). Aortic vasorelaxations induced by PVATRF-and PAME-containing Krebs solutions were not affected after heating at 70°C but were equally attenuated after hexane extractions. Culture mediums of differentiated adipocytes, but not those of fibroblasts, contained significant PAME and caused aortic vasorelaxation. The PVAT of spontaneously hypertensive rats released significantly less PVATRF and PAME with an increased release of angiotensin II. In addition, PAME-induced relaxation of spontaneously hypertensive rats aortic smooth muscle diminished drastically, which was ameliorated significantly by losartan. Conclusions-We found that PAME is the PVATRF, causing vasorelaxation by opening voltage-dependent K ϩ channels on smooth muscle cells. Diminished PAME release and its vasorelaxing activity and increased release of angiotensin II in the PVAT suggest a noble role of PVAT in pathogenesis of hypertension. The antihypertensive effect of losartan is attributed partly to its reversing diminished PAME-induced vasorelaxation. (Circulation. 2011;124:1160-1171.) Key Words: angiotensin II Ⅲ fatty acids Ⅲ hypertension Ⅲ potassium ion channels Ⅲ vasomotor tone Ⅲ vasorelaxation Ⅲ losartan T he systemic blood vessels are surrounded by various amounts of perivascular adipose tissue (PVAT). Since the first report by Soltis and Cassis in 1991 that PVAT attenuated contraction of aortic rings to norepinephrine, 1 it has been well accepted that the anticontractile effect of PVAT is due to release of relaxing factor(s) from these adipocytes. 2 The vasodilation induced by PVAT-derived relaxing factor (PVATRF) is independent of the endothelium, cyclooxygenase, or cytochrome P450 pathway. 2,3 The general consensus is that PVATRFinduced vasodilation is due to opening of potassium channels on the smooth muscle cells. [2][3][4][5] The chemical identity of the PVATRF, however, remains unknown. Clinical Perspective on p 1171Our recent studies using superfusion bioassay cascade technique have demonstrated release of an endogenous potent vasodilator, palmitic acid methyl ester (PAME), from the superior cervical ganglion and retina of the rat. 6,7 Because PAME is hydro...

Fatty acid methyl esters as a potential therapy against cerebral ischemia

“…Lin et al (2008) first reported that PAME released from SCG (the largest cervical ganglion in the sympathetic tract (Lee et al, 2011a(Lee et al, , 2011bLee et al, 2012;Wu et al, 2014)) is a novel vasodilator (Lin et al, 2008). Exogenous application of PAME directly onto the rabbit or rat thoracic aorta induced vasodilation in a concentration-dependent manner (Lin et al, 2008;Lee et al, 2010;Lee et al, 2011c). The EC 50 value (the concentration that induces 50% of the maximum relaxation) for PAME-elicited aortic vasodilation is 0.19 nM which is at least 178 times (vs. 34.8 nM) lower than that of sodium nitroprusside (NO donor)-induced vasodilation (BrizzolaraGourdie and Webb, 1997; Lin et al, 2008) indicating that PAME is a potent vasodilator.…”

“…However, it has also been shown that PAME spontaneously released from the retina is described as the retinaderived relaxing factor (Lee et al, 2010) which induces potent vasodilation in the pre-contracted rat aorta suggesting an important role in retinal circulation (Lee et al, 2010). In addition, PAME is also released from perivascular adipose tissue (PVAT), which has been reported to be PVAT-derived relaxing factor (Lee et al, 2011c) regulating systemic blood pressure. It is interesting to note that the reduction of PAME released from PVAT can be observed in genetic hypertensive rats (Lee et al, 2011c).…”

“…In addition, PAME is also released from perivascular adipose tissue (PVAT), which has been reported to be PVAT-derived relaxing factor (Lee et al, 2011c) regulating systemic blood pressure. It is interesting to note that the reduction of PAME released from PVAT can be observed in genetic hypertensive rats (Lee et al, 2011c). Furthermore, exogenous application of PA failed to induce aortic vasodilation (Blondeau et al, 2007;Lin et al, 2008) indicating that the methylation of PA is essential for vasodilation and PAME's bioactivity.…”

“…The release of PAME from the SCG, PVAT, and retina, however, dramatically decreased in calcium-free Krebs' solution (Lee et al, 2010(Lee et al, , 2011cLin et al, 2008) indicating that calcium may be important for PAME release. Furthermore, the release of PAME from the SCG was reduced in the present of myosin light chain inhibition (Lin et al, 2008), which prevents synaptic vesicle pool mobilization (Ryan, 1999) suggesting that the release of PAME is possibly linked to synaptic vesicle exocytosis.…”

“…The exact mechanisms of PAME-induced vasodilation are not well-known. However, D108, page 3 of 6 Dossier R. Hui-Chao Lee et al: OCL 2016, 23(1) D108 PAME-induced aortic vasodilation is inhibited by voltagegated potassium (Kv) channel blockers such as tetraethylammonium and 4-aminopyridine in a concentration-dependent manner (Lee et al, 2010(Lee et al, , 2011c indicating that PAME may induce aortic vasodilation via opening Kv channels on vascular smooth muscle. The vasodilatory properties of PAME offer a potential therapeutic opportunity in the treatment against cerebral ischemia-induced hypoperfusion consequently promoting brain injury.…”