Endothelial dysfunction in hypertension: fact or fantasy?

Endothelial cells are known to have important regulatory effects on the cardiovascular system through the release of vasodilator and vasoconstrictor factors [1]. In small arteries, the endothelium appears to exert a key role in the imbalance between vasoconstriction and vasodilatation. Acetylcholine and bradykinin are able to induce the release of endothelium-derived relaxing factors, and therefore the vasodilator response to these substances may be considered a useful tool to evaluate endothelial function. In fact, acetylcholine stimulates the release of nitric oxide (NO), mediated by M3 receptors. The development of high blood pressure in humans appears to be associated with an impairment of endothelial function, as evaluated by the vasodilator response to acetylcholine infused into the brachial artery [2–4]. Using the same technique, a significant impairment of endothelial function was also observed in secondary forms of hypertension [2]. The assessment of endothelial function in small resistance arteries (lumen diameter 100–300 μm), both in normal subjects or in patients with cardiovascular disease, is not an easy task [5]. The available data have been obtained by testing the in-vitro vascular response to agonist-stimulating vasodilator endothelial receptors (acetylcholine, bradykinin, substance P, etc.). Small resistance vessels can be obtained from surgical biopsies and mounted on wire or perfusion-pressure micromyographs. In at least two studies in which the vasodilator response to acetylcholine in human small resistance arteries was evaluated, a significant impairment of endothelial function was observed both in primary [6,7] and secondary hypertension [7]. However, other studies failed to observe significant differences in endothelium-dependent vasodilatation when comparing hypertension with normotension, both in humans [8–10] and in animal models [11]. Several reasons may be advocated to explain the discrepancies observed, including the doses of the agonist used, the age of the control groups (ageing is one of the most important factors able to induce endothelial dysfunction) [12] and the possible heterogeneity of endothelial dysfunction in different vascular districts [13]. Therefore, although the evidence predominantly points towards the presence of an evident endothelial dysfunction in the microcirculation, both in humans and in animal models of genetic or experimental hypertension, the issue remains, at least in part, controversial [14–16]. Endothelial dysfunction in hypertension: a primary or a secondary phenomenon? It is presently unclear whether endothelial dysfunction is a primary abnormality or a consequence of the elevated blood pressure values. Data in animal models of genetic hypertension are in favour of direct damage of the endothelial cells secondary to a prolonged increase of the haemodynamic load and shear stress [17–20]. In patients with phaeochromocytoma, primary aldosteronism or renovascular hypertension [7,21], an impairment of the vasodilator response to acetylcholine was found despite there being no genetic predisposition to hypertension. However, in normotensive offspring of hypertensive parents, an early alteration of endothelium-dependent vasodilatation in the forearm was observed [22], thus suggesting a possibly relevant role of genetic mechanisms in the genesis of endothelial dysfunction in hypertension. The identification of genetic markers of endothelial dysfunction has, as yet, been unsuccessful [23]. Endothelial dysfunction: underlying mechanism in renovascular hypertension The possible role of the mechanisms of activation of neurohumoral systems in the genesis of endothelial dysfunction has been investigated in patients with secondary forms of hypertension (phaeochromocytoma, primary aldosteronism, renovascular hypertension), as well as control patients with essential hypertension, or normotensive subjects [7,21]. Patients with renovascular hypertension demonstrated the most pronounced vascular structural alterations, as indicated by a more evident increase in the media to lumen ratio of small resistance arteries compared to essential hypertensive patients or patients with phaeochromocytoma. Despite the quantitative and qualitative difference in vascular structure among the different groups, endothelial function, as explored by the vasodilator response to acetylcholine, was similarly impaired in the different hypertensive groups [24]. Therefore, activation of the renin–angiotensin–aldosterone system or vascular structure does not appear to be the major determinant of endothelial dysfunction, at least in subcutaneous small resistance arteries. New contributions to the controversy In this issue of the journal, Stankevicious et al. [25] address several important aspects regarding endothelial dysfunction in a animal model of renovascular hypertension (one kidney, one clip Sprague–Dawley rats). The authors were able to confirm the presence of endothelial dysfunction in mesenteric arteries, thus supporting the hypothesis that alterations of endothelial function in hypertension are likely to be a secondary phenomenon, probably as a consequence of increased blood pressure values. Furthermore, Stankevicious et al. [25] make a valuable attempt to identify the mechanisms underlying endothelial dysfunction in renovascular hypertension. Their findings are partially surprising, since an altered vasodilator response to acetylcholine was demonstrated to be associated with reduced NO release from the endothelium, rather than an excessive breakdown due to oxidative stress. Angiotensin II was previously demonstrated to increase oxidative stress; therefore, a pronounced activation of the renin–angiotensin–aldosterone system should theoretically induce a reduction in NO bioavailability by increasing NO degradation [26]. In the present study, no evidence of increased degradation of NO by superoxide anions or other free radicals was observed, and the superoxide scavenger superoxide dismutase had no effect on endothelial function. These observations may have important clinical consequences, and suggest that therapeutic strategies aimed at protecting the endothelium in renovascular hypertension should point towards a correction of a decreased synthesis or release of NO, rather than preserving vessels from oxidative stress. As a consequence, no beneficial effects of vitamin C or E, or other antioxidants, should be expected. However, some additional issues and some limitations of the study should be taken into account in the interpretation of the data provided [25]. First, before drawing definite conclusion, the authors’ observations should be extended to human renovascular hypertension. The mechanisms underlying endothelial dysfunction in humans may be subtly different. Second, no information about the possible contribution of cyclooxygenase-dependent, endothelial-derived contracting factors [27] is provided, since all the experiments were peformed in the presence of indomethacine in order to avoid the possible confounding effect of the endothelial production of vasoconstricting factors. Third, and as properly acknowledged by the authors themselves, the study does not completely rule out a possible role of oxidative stress in the genesis of endothelial dysfunction in the experimental models examined. Finally, the reduced NO release and relaxation persisted in the presence of substrate for NO release (l-arginine). Therefore, the correction of the observed abnormality should imply the stimulation of NO synthase. However, no direct and selective stimulator of NO synthase is presently available (calcium ionophors and tetrahydrobiopterin can hardly be considered direct or selective); moreover, biochemical controls of NO synthesis are presently still under investigation. In conclusion, relevant information is provided by the present study; however, the possible clinical significance of the authors’ observations is uncertain. In addition, many aspects related to the mechanisms involved in the genesis and maintenance of endothelial dysfunction in small vessels deserve further investigation. This issue is far from being trivial, since endothelial dysfunction in hypertension is highly likely to have independent prognostic significance [28], as demonstrated by other recent studies [29,30].