Involvement of neuroadrenergic factors in hypertensive vascular remodelling

It is a time-honored notion that the hyperadrenergic state characterizing hypertension may trigger the development, as well as the progression, of hypertension-related target organ damage, thereby promoting cardiac and vascular structural alterations [1–3]. As far as myocardial tissue is concerned, conclusive evidence is now available that the adrenergic activation may favour the cardiac alterations leading to hypertension-related morbidity and mortality, such as left ventricular hypertrophy, independently of the blood pressure elevation. This has been recently strengthened by evidence indicating that, in hypertensive patients with left ventricular hypertrophy, left ventricular mass index directly correlates with the amount of norepinephrine ‘spilling-over’ from cardiac sympathetic nerve endings, as well as with the peripheral sympathetic nerve firing rate directly quantified by the microneurographic approach [4–6]. Evidence collected in different animal models supports the concept that neuroadrenergic mechanisms do exert prohypertrophic effects not only at the cardiac, but also at the vascular level. This is because sympathetic denervation has been shown to trigger a reduction in arterial wall-to-lumen ratio and in the rate of thymidine incorporation in vascular smooth muscle cells [7,8]. Furthermore, cervical gangliectomy reduces the wall-to-lumen ratio of the cerebral vessels of the ipsilateral side in stroke-prone hypertensive rats, and chemical sympathectomy increases arterial distensibility in the carotid and femoral vascular districts in Wistar–Kyoto rats [9,10]. Whether sympathetic influences also exert prohypertrophic vascular effects in human hypertension has been less univocally demonstrated. For example, while it has been shown that beta adrenergic receptors play a major role in the regulation of human vascular smooth muscle cell growth [11], it has also been shown that beta-blocking drugs are unable to exert any beneficial effect on hypertension-related structural alterations of small arteries in hypertensive patients [12,13]. In the present issue of the journal, Porteri et al. [14] add interesting new data to the above-mentioned controversy by reporting the results of a study using the miomyographic technique to assess the morphologic characteristics and the ‘remodelling index’ of small resistance arteries in normotensive subjects, and in patients with essential hypertension or with a secondary hypertensive state due to an adrenal pheochromocytoma. As expected, media-to-lumen ratio was significantly greater in patients with essential hypertension or pheochromocytoma compared to normotensive individuals. However, media cross-sectional area of the examined vessels was almost superimposable not only in the bioptic specimens of normotensive and essential hypertensive subjects, but also in patients with pheochromocytoma. Taken together, these findings suggest that even when markedly activated, such as in pheochromocytoma, the adrenergic nervous system does not appear able to trigger either vascular smooth muscle cell hypertrophy or a hypertrophic remodelling of the vessel wall. Can these data be regarded as meaning that the sympathetic nervous system does not play a causative role in the process of vascular remodelling and growth? A number of questions and considerations and a proposed working hypothesis, based on the results of the study by Porteri et al. [14], are proposed suggesting that this is not the case. Sympathetic activity and vascular remodelling: questions and considerations At least three questions can be advanced in an attempt to extrapolate more general conclusions about the relationships between sympathetic neural factors and hypertension-related vascular structural changes from the findings of this specific study. Does pheocromocytoma represent the ‘gold standard’ model for studying the cardiovascular effects of a hyperadrenergic state? How can the similar left ventricular mass indices in essential hypertensives and pheocromocytoma patients be explained? Are the functional and structural alterations detected in the small resistance arteries of the subcutaneous fat tissue representative of other districts? Although initially appearing somewhat provocative, the first question refers to an important point, namely the fact that the data obtained by Porteri et al. [14] refer to adrenal pheocromocytoma secreting epinephrine and, to a lesser extent, norepinephrine. Given that the cardiovascular effects of the two adrenergic neurotrasmitters are remarkably different (and in some instances, even opposite) [15], it is unknown whether the alterations of the small arteries described in the present study can be also seen in tumours mainly secreting norepinephrine. In addition, it should remebered that, in pheochromocytoma, the abnormal synthesis and secretion of catecholamines from the adrenal mass triggers a number of neuroadrenergic alterations, such as the down-regulation of the adrenergic receptors [16] and the inhibition of the central sympathetic outflow [17], which can be hardly regarded as typical features of a ‘physiological’ model of a hyperadrenergic state. The need for caution when considering pheochromocytoma as the ‘gold standard’ model for assessing the cardiovascular effects of a hyperadrenergic state is further emphasized by the finding by Porteri et al. [14] that, despite very high circulating levels of catecholamines which do exert prohypertrophic effects on the myocardial tissue [18–20], their pheochromocytoma patients displayed values for the left ventricular mass index similar to (or even lower than) those found in essential hypertensive individuals of their study. The reasons responsible for this finding, which has also been reported in other studies [16,21], are not easily determined, although the disease duration, the intermittent or stable pattern of catecholamine secretion and the adrenal or extra-adrenal anatomical location of the tumour (and thus the epinephrine or norepinephrine hypersecretion) may certainly play a role. Finally, as far as the issue of the more general representativity of the small arteries in subcutaneous fat tissue is concerned, it is still unknown whether the alterations detected in these small arteries in a number of diseases closely resemble those occurring in the small arteries of other cardiovascular districts [22]. However, recent data suggest that a parallelism exists between structural alterations in the small arteries of the subcutaneous tissue and those detected in the coronary circulation [23]. Vascular remodelling and neurohumoral activation: a working hypothesis The process of vascular remodelling has been described in several different models some years ago [24,25], although the precise mechanism(s) responsible for its various patterns (inward eutrophic, hypotrophic and hypertrophic remodelling) are far from being clearly elucidated. The data provided by the present study [14], and those collected by the same group of investigators in patients with renovascular hypertension [26] characterized by a marked stimulation of the renin–angiotensin system, allow the working hypothesis depicted in Figure 1 to be advanced. Namely, that while hypertrophic inward remodelling is triggered by high circulating levels of angiotensin II, eutrophic inward remodelling might depend on elevated levels of catecholamines. Future studies, performed in other clinical conditions characterized by renin–angiotensin or sympathetic activation, will clarify the above-mentioned hypothesis and reveal the neurohumoral mechanisms involved in the third pattern of inward remodelling (i.e. the hypotrophic one).Fig. 1: Scheme illustrating the different forms of inward remodelling and its hypothesis of neurohumoral determination. Figure adapted with permission [25]. RAAS, Renin–angiotensin aldosterone system; SNS, sympathetic nervous system; ?, unknown factors.