Resveratrol and vasorelaxation

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Resveratrol was able to inhibit the production of endogenous vasoconstrictors and thereby regulates vasomotion which is impaired in atherosclerosis. The key regulators of vasomotor function are the vasodilatator NO and the vasoconstrictor endothelin-1 (ET-1). In VSMC, oxidative stress increases the ET-1, which is involved in endothelial dysfunction, generation and autocrine ET-1 activity. Resveratrol inhibits strain-induced ET-1 secretion [83, 84], ET-1 mRNA level, and ET-1 promoter activity [84]. This inhibition of strain-induced ET-1 gene expression was partially due to resveratrol attenuation of activator protein 1 (AP-1) binding activity and resveratrol interference in the ERK1/2 pathway through attenuation of ROS formation [84] (figure 5). Resveratrol inhibits ET-1 surproduction and cytosolic phospholipase A₂ (PLA₂) activity stimulated by oxidative stress [83]. ET-1 expression can be induced by several substances such as angiotensin II (Ang II), thrombin, PDGF-A, and TNFa [85]. So, resveratrol can reduce ET-1 expression by its action on the latter factors. Indeed, resveratrol can act on Ang II. Angiotensin II-induced hypertrophy of vascular VSMCs is a pivotal step in the development of CHDs. Resveratrol could fight angiotensin II (Ang II)-induced VSMC hypertrophy by interfering with the phosphatidylinositol 3-protein (PI3K)/Akt and p70 ribosomal protein S6 kinase (p70(S6K)) [77, 86]. Indeed, resveratrol is able to attenuate the phosphorylation of p70(S6K) as well as the phosphorylation of Akt/ protein kinase B (PKB) and ERK1/2, both essentially involved in Ang II-mediated hypertrophy (figure 5). This action on Ang II by resveratrol can protect from cardiac fibrosis. Indeed, cardiac fibrosis results of a prolonged activation of cardiac fibroblats (CFs) leading to a reduction of myocardial contractile function. Resveratrol inhibits Ang II-induced ERK1/2 and ERK kinase activation in CFs [87]. Moreover, pretreatment of CFs with resveratrol reduced both Ang II- and TGFb-induced CF differenciation to the myofibroblast phenotype, indicated by a reduction in alpha-smooth muscle actin expression and stress fiber organization in CFs. So, resveratrol appeared to act as an anti-fibrotic agent in the myocardium. Furthermore, the reduction of Ang II concentrations would reduce the increase of NADPH oxidase-derived ROS.

ET-1 activates specific receptors, designated as ET_A and ET_B [88]. So, resveratrol by its action on PLA₂ and other signalling pathways appears to protect against VSMC contraction mediated by the ET_A-receptor.

The inhibition of strain or the induction of vasorelaxation can also be dependent on NO production, Na⁺ concentrations or cGMP pathways. For the NO production, it has been clearly documented that resveratrol can modulate the level of NO by its action on both eNOS and iNOS. Under normal conditions, ECs produce NO at a low level to control vessel dilatation. However, in atherosclerosis, a high level of NO has been found within early lesions and advanced atheroma even though expression of eNOS is reduced. On the contrary, the inductible Ca2+-independent NOS, also known iNOS, was increased. It has been shown that resveratrol can cause NO-mediated relaxation of precontracted endothelium-intact rat aorta through an increase of NO via eNOS [89-93]. At molecular level, resveratrol enhanced eNOS expression and inhibited iNOS expression by an action on their promoter (see below resveratrol and nuclear targets). In fact, resveratrol increases the activity of the eNOS promoter and eNOS mRNA stabilisation [94]. The vasorelaxation mediated by the polyphenol was reversed by the constitutive Ca²⁺-dependent NOS (cNOS). The compound also induces a NO-independent vasodilatation on denuded aorta, and the vasorelaxative activity of resveratrol depends also on direct stimulation of K⁺/Ca²⁺ channels in ECs [95]. So, it seems that the ability of resveratrol to modulate calcium channels in ECs could contribute to control the vasorelaxion mediated by nitric oxide (NO) (see below resveratrol and platelet aggregation).

Concerning the cGMP pathway, resveratrol increases cGMP in coronary arteries, mostly by activation of pGC [96]. Resveratrol activates membrane-bound guanylate cyclase GC-A, the receptor for atrial natriuretic factor (ANF) [97]. At molecular level, the cGMP/kinase-G is an antiproliferative signaling in SMCs and it dilates blood vessels through the reduction of intracellular calcium. The cytotastic actions of cGMP in SMCs involved apoptosis, inhibition of PI3K and mitogen-activated protein kinases (MAPKs) interfering with the cell-cycle machinery [98]. So the activation of pGC by resveratrol triggers vasorelaxant responses that remain effective in endothelium-disrupted arteries.

Resveratrol could also influence the vasorelaxation through an action on the activity of BK(Ca) channels which are functionally expressed in vascular ECs; it controls K⁺ efflux and affects intracellular Ca²⁺ concentration. In fact, resveratrol opens large and small conductance Ca²⁺-activated K⁺ (BKCa) channels, but not ATP-sensitive K⁺ channels [99] and increases the activity of large conductance BKCa channel in ECs [95, 100]. The resveratrol-stimulated increase in the channel activity was independent of internal Ca²⁺. So, the increase in K⁺ efflux through resveratrol-induced stimulation of KCa channels in ECs may contribute to produce vasorelaxation.