The Vascular Effects of Isolated Isoflavones-A Focus on the Determinants of Blood Pressure Regulation

Abstract

Isoflavones are phytoestrogen compounds with important biological activities, including improvement of cardiovascular health. This activity is most evident in populations with a high isoflavone dietary intake, essentially from soybean-based products. The major isoflavones known to display the most important cardiovascular effects are genistein, daidzein, glycitein, formononetin, and biochanin A, although the closely related metabolite equol is also relevant. Most clinical studies have been focused on the impact of dietary intake or supplementation with mixtures of compounds, with only a few addressing the effect of isolated compounds. This paper reviews the main actions of isolated isoflavones on the vasculature, with particular focus given to their effect on the determinants of blood pressure regulation. Isoflavones exert vasorelaxation due to a multitude of pathways in different vascular beds. They can act in the endothelium to potentiate the release of NO and endothelium-derived hyperpolarization factors. In the vascular smooth muscle, isoflavones modulate calcium and potassium channels, leading to hyperpolarization and relaxation. Some of these effects are influenced by the binding of isoflavones to estrogen receptors and to the inhibition of specific kinase enzymes. The vasorelaxation effects of isoflavones are mostly obtained with plasma concentrations in the micromolar range, which are only attained through supplementation. This paper highlights isolated isoflavones as potentially suitable alternatives to soy-based foodstuffs and supplements and which could enlarge the current therapeutic arsenal. Nonetheless, more studies are needed to better establish their safety profile and elect the most useful applications.

Keywords: endothelium; estrogen receptor; ion channels; isoflavones; tyrosine kinase; vasorelaxation.

Figure 1

Molecular structure of the five main isoflavones in their aglycone form (genistein, daidzein, glycitein, formononetin, biochanin A) and of the metabolites S(−)-equol, dehydroequol, dihydrodaidzein, and tetrahydrodaidzein.

Figure 2

(a) Proposed vasorelaxation mechanisms for genistein (GNT); (b) proposed vasorelaxation mechanisms for daidzein (DDZ); (c) proposed vasorelaxation mechanisms for formononetin (FMN); (d) proposed vasorelaxation mechanisms for biochanin A (BCA); (e) proposed vasorelaxation mechanisms for glycitein (GCT), equol (EQL), dehydroequol (DEQL), dihydrodaidzein (DHDDZ), and cis- and trans-tetrahydrodaidzein (cis-/trans-THDDZ). 5-HTR—serotonin receptor; α₁R—alpha-1 adrenergic receptor; cGMP—cyclic guanosine monophosphate; CFTR—cystic fibrosis transmembrane conductance regulator; CM—calmodulin; CV-1—caveolin-1; CYP450 – cytochrome P450 enzymes; EETs – epoxyeicosatrienoic acids; eNOS—endothelial nitric oxide synthase; EDHFs—endothelium-derived hyperpolarization factors; ER—estrogen receptor; HP—hyperpolarization; MAPK—mitogen associated protein kinase; NO—nitric oxide; ROCC—receptor-operated calcium channel; TyrK—tyrosine kinase; VGCC—voltage-gated calcium channel.