Increased arterial stiffness is influenced by both functional and structural properties of the vessel wall, including changes in content of smooth muscle, elastin and collagen, reduced endothelial production of NO and increased release of endothelin-1 or AngII (angiotensin II). The RAS (renin–angiotensin) system is likely to be central to increases in arterial stiffness, since the changes in arterial structure observed with enhanced AngII activity are similar to the same pathophysiological changes that contribute to arterial stiffness. The role of AT1R and AT2R (AngII type 1 and type 2 receptors respectively) in the development of arterial stiffening, particularly in the early stages of insulin resistance, is however unclear. In this issue of Clinical Science, Brillante and co-workers have observed that in insulin-resistant subjects exhibiting reduced arterial stiffness, wave reflection from small-to-medium-sized, but not large, arteries was increased following separate intravenous infusions of AngII, the selective AT2R inhibitor PD123319 and the NO inhibitor L-NMMA (NG-monomethyl-L-arginine) in comparison with normal healthy age- and sex-matched controls. These increases probably reflect increased AT1R and AT2R expression/activity in addition to up-regulation of basal NO release in the small-to-medium-sized arteries. These changes may be compensatory mechanisms related to early vascular damage and may have clinical implications for treatment in hypertensive patients with evidence of the metabolic syndrome.

Arterial stiffness is a strong prognostic indicator in individuals with or at risk of coronary artery disease and has been demonstrated consistently in individuals with T2DM (Type 2 diabetes mellitus) and, more recently, in individuals with insulin resistance, independently of obesity and fasting glucose [1]. Arterial stiffness is influenced by both functional and structural properties of the vessel wall, which are determined by its content of smooth muscle, elastin and collagen. The fracturing of elastin fibres and qualitative changes in collagen that occur with aging lead to a gradual increase in arterial stiffening. Arterial stiffness is also related to endothelial function; reduced endothelial production of NO and increased release of endothelin-1 or AngII (angiotensin II) can affect arterial stiffness via a vasotonic effect on VSMCs (vascular smooth muscle cells) [2].

AngII is likely to be central to the structural and functional changes observed in large arteries via increases in AT1R (AngII type 1 receptor) activity [3]. The underlying changes in arterial structure observed with enhanced AngII activity are similar to the same pathophysiological mechanisms that contribute to arterial stiffness, including collagen degradation, smooth muscle proliferation, fibrosis and cross-linking of VSMCs and collagen fibres [4]. Individuals with T2DM have an increased sensitivity to AngII-induced vasoconstriction, suggesting an up-regulation of AT1Rs in large arteries. Treatment with AT1R blockers for 6 months decreased arterial stiffness, independently of blood pressure reduction, and also increased serum adiponectin, suggesting improved insulin sensitivity, in patients with essential hypertension [5]. Early atherosclerotic lesions and/or microvascular damage may cause up-regulation of local AT1R and AT2R (AngII type 2 receptor) activity [6], the latter mediating local vasodilation. Evidence of vascular damage causing arterial stiffening in insulin resistance is supported by reduced insulin resistance and large artery stiffness in non-diabetic insulin-resistant subjects using PPARγ (peroxisome-proliferator-activated receptor γ) agonists, which are expressed in endothelial cells and VSMCs and are known to have various anti-atherogenic effects [7]. The variety of sites and mechanisms via which the RAS (renin–angiotensin system) influences arterial stiffness is emphasized by the ability of AT1R blockers and ACE (angiotensin-converting enzyme) inhibitors to exert additive or synergistic effects on arterial stiffness independently of blood pressure reduction, despite affecting the same pressor system [8]. Short-term functional effects, including VSMC relaxation and improved endothelial function, are combined with long-term structural effects relating to arterial wall thickness, collagen content and reversion of VSMC hypertrophy.

Both large and small/medium arterial stiffness may be examined using the DVP (digital volume pulse) waveform obtained from finger photoplethysmography [9]. The DVP consists of a forward travelling wave plus a backward travelling wave that arises from wave reflections in a similar manner to the pulse pressure waveform. With arterial stiffening, pulse wave reflection occurs relatively sooner, causing the reflected wave to overlap the forward travelling wave and a loss of the second peak. The distance between the first and second peak relates to the speed of the pressure wave and is used to derive the SI (stiffness index), an indicator of large artery stiffness. The RI (reflection index) is the height of the second peak relative to the first peak and is dependent on the extent of vasodilation and wave reflection in the small-to-medium-sized arteries [9]. Acute increases in RI or SI denote increased wave reflection and a reduction in arterial smooth muscle relaxation.

In this issue of Clinical Science, Brillante et al. [10] report a cross-sectional comparison study of subjects without and with insulin resistance in which they examined small-to-medium and large arterial stiffness as well as AT1R, AT2R and basal NO activity. Compared with normal control subjects, insulin-resistant subjects had slightly lower small-to-medium and large arterial stiffness, as assessed by RI and SI respectively. Following separate intravenous infusions of both AngII and the AT2R inhibitor PD123319, RI, but not SI, increased in the insulin-resistant subjects compared with controls, indicating an increased expression of both AT1R and AT2R in small-to-medium-sized, but not large, arteries among the insulin-resistant subjects. The increases in wave reflection following drug administration, which were also independent of changes in systemic vascular resistance, are likely to be a consequence of vasoconstriction. NO modulates the generation of AngII and also acts as a functional antagonist at VSMCs [11]; increasing the availability of AngII or blocking AT2Rs, as in the study by Brillante et al. [10], may therefore reduce NO availability and increase vasoconstriction and wave reflection.

Brillante et al. [10] considered the possibility that the putative increases in AT2R activity may represent a compensatory mechanism to counteract the negative effects of increased AT1R expression and activity. Similarly, the greater increase in RI observed in the insulin-resistant subjects following inhibition of NO release via intra-arterial infusion of L-NMMA (NG-monomethyl-L-arginine), an NO inhibitor, suggests a compensatory increase in NO. Previous studies have observed increases in both NO and non-NO vasodilators in subjects with T2DM [12,13]. Individuals with T2DM without autonomic neuropathy were observed to have increased basal FBF (forearm blood flow) compared with non-diabetic healthy individuals [13]. Basal FBF with NO and PGI2 (prostaglandin I2) inhibition, attained using infusion of L-NMMA and co-administration of aspirin respectively, was also higher in the diabetic subjects, and pulse pressure was predictive of these responses. The change in FBF following L-NMMA was, however, greater in control subjects. This suggested an increased availability of non-NO vasodilator agents, in particular endothelium-derived hyperpolarizing factor. In contrast with the findings of Brillante et al. [10], basal NO was not higher in the subjects with T2DM, as inhibition of basal FBF was not increased following infusion of L-NMMA alone. It is possible that continued up-regulation of basal NO release may eventually be exhausted, leaving dependence on other non-NO vasodilators to provide adequate blood flow and vasodilation.

Increased medium-sized arterial compliance has been observed previously in insulin-resistant states. Isobaric distensibility and compliance of the medium-sized radial artery assessed at the same level of blood pressure using distensibility and compliance pressure curves was either unchanged or higher in patients with untreated mild or moderate essential hypertension compared with age-matched normotensive subjects [14]. Similarly, compliance in the radial artery was considerably increased in young obese insulin-resistant subjects compared with lean controls [15]. Together, these findings indicate that compensatory mechanisms may exist in the early stages of insulin resistance, which, if left untreated, are eventually overcome, leading to increased arterial stiffening and hypertension.

If the findings and data interpretation from Brillante et al. [10] prove correct, AT1R blockers might be a preferred treatment for hypertensive patients with evidence of the metabolic syndrome. By negating the increases in AT1R activity, they provide the potential to benefit from the compensatory increases in AT2R activity. Some caution to the findings should, however, be applied, since the authors [10] did not provide any data on reproducibility of the DVP involving a change after drug administration and, in particular, within the setting of insulin resistance. Considerable variability in techniques related to vascular function that require intra-arterial or intravenous drug administration is common and may lead to Type 1 errors when the sample size is small; however, the consistency of the results using different doses of AngII and PD123319 support the authors' conclusions [10].

In summary, Brillante et al. [10] provide evidence of increased AT1R and AT2R activity in addition to potential up-regulation of basal NO release in the small-to-medium-sized arteries of young individuals with insulin resistance. These changes may be compensatory mechanisms related to early vascular damage and may also partially explain the reduced small-to-medium-sized arterial stiffness compared with healthy controls in this particular population. In addition to gaining further insight into the influence of the RAS on the modulation of arterial stiffness and the implications for treatment among patients with hypertension and the metabolic syndrome, the study [10] also highlights the need to exert caution in extrapolating arterial SI data to cardiovascular risk in individuals with early stage insulin resistance.

Abbreviations

     
  • AngII

    angiotensin II

  •  
  • AT1R

    AngII type 1 receptor

  •  
  • AT2R

    AngII type 2 receptor

  •  
  • DVP

    digital volume pulse

  •  
  • FBF

    forearm blood flow

  •  
  • L-NMMA

    NG-monomethyl-L-arginine

  •  
  • RAS

    renin–angiotensin system

  •  
  • RI

    reflection index

  •  
  • SI

    stiffness index

  •  
  • T2DM

    Type 2 diabetes mellitus

  •  
  • VSMC

    vascular smooth muscle cell

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