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. 2007 Oct 25;586(Pt 2):319–324. doi: 10.1113/jphysiol.2007.145698

Physical (in)activity and endothelium-derived constricting factors: overlooked adaptations

D H J Thijssen 1, G A Rongen 2, P Smits 2, M T E Hopman 1
PMCID: PMC2375603  PMID: 17962322

Abstract

The inner surrounding of arterial vessels, the endothelium, is optimally located to detect changes in blood characteristics or blood flow that may result from changes in physical activity or from diseases. In response to physical stimuli, the endothelium varies its release of circulating vasoactive substances and serves as a source of local and systemic endothelium-derived dilator and vasoconstrictor factors. Endothelial dysfunction is one of the earliest markers of vascular abnormalities observed in cardiovascular disease and ageing. Exercise training is an efficient therapeutic strategy to improve endothelial function. Traditionally, studies on endothelial dysfunction and physical (in)activity-related effects on vascular adaptations are primarily focused on vasodilator substances (i.e. nitric oxide). One may suggest that augmentation of vasoconstrictor pathways (such as endothelin-1 and angiotensin II) contributes to the endothelial dysfunction observed after physical inactivity. Moreover, these pathways may also explain the exercise-induced beneficial cardiovascular adaptations. This review summarizes the current knowledge on the effects of physical (in)activity on several endothelium-derived vasoconstrictor substances.

The importance of physical inactivity as a modifiable behavioural risk factor for cardiovascular disease is widely recognized (Wannamethee & Shaper, 2001). The endothelial function is suggested to underlie the physical activity-induced vascular adaptations. Situated between the circulating blood and the surrounding tissue, the endothelium is optimally located to detect changes in blood contents or blood flow that may result from physical (in)activity. In response, the endothelium varies its release of substances that modulate vascular tone (e.g. vasodilators and vasoconstrictors), structure (proliferative) or blood characteristics (e.g. coagulation pathway, inflammatory control).

Vasodilators in general, and nitric oxide (NO) specifically, have been the primary focus in explaining the mechanisms of vascular changes resulting from activity and inactivity. Several animal studies and human in vivo invasive studies (using pharmacological blockade or stimulation of vasodilators) have assessed the role of these vasodilators in the regulation of vascular tone. In an excellent recent review for this journal, Green et al. (2004) summarized these studies and described the importance of the endothelium-derived NO pathway for exercise-induced cardiovascular adaptations. Whilst the effects of the vasoactive substances on vascular tone and vascular growth largely depend on a delicate balance between dilators and constrictors (Spieker et al. 2006) (Fig. 1), there is a predominance of studies focusing on vasodilators (primarily NO) to explain exercise-induced adaptations. It may well be that exercise-induced changes are, at least in part, related to other pathways than NO. In addition, physical inactivity results in cardiovascular adaptations that are the opposite of the effects of exercise training. Given the effects of exercise training on the NO pathway, vascular changes to physical inactivity were hypothesized to result from an inhibition of the NO pathway. However, we (de Groot et al. 2004; Bleeker et al. 2005) and others (Bonnin et al. 2001) found a preserved contribution of NO to vascular tone and preserved NO-dependent endothelial function during inactivity.

Figure 1. The delicate balance between endothelium-derived vasoactive substances contributing to the vascular tone.

Figure 1

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The above results suggest that other pathways than solely vasodilator mechanisms may be involved in cardiovascular adaptation to changes in physical activity. In this review, we discuss findings regarding the contribution of endothelium-derived constricting factors in explaining cardiovascular adaptations during physical (in)activity in healthy subjects and in cardiovascular disease. Studies discussed in this review article related to (changes in) physical activity pertain to dynamic exercise rather than resistance exercise.

Endothelium-derived vasoconstricting factors

Endothelin-1

Endothelin-1 (ET-1) is the predominant isoform of the endothelin family and is mainly secreted by the endothelium (Yanagisawa et al. 1988) in response to a variety of stimuli (Table 1). The release of ET-1 results in activation of two receptors: ETA and ETB. Activation of the ETA and ETB receptors on the smooth muscle cell mediates a sustained constrictor action of ET-1. The ETB receptors on the endothelium mediate the release of the dilators NO and prostacyclin, but also mediate the rapid uptake of ET-1 (Haynes & Webb, 1998). Therefore, the endothelial ETB receptor largely opposes the vascular effect of smooth muscle cell-located ETA/B receptors. In addition to the direct vascular effects, ET-1 induces vascular smooth muscle cell proliferation and growth in a dose-dependent manner (Komuro et al. 1988).

Table 1.

Physical stimuli that stimulate or inhibit the pathways of endothelin-1 and angiotensin II

Humoral stimuli Physical/exogenous stimuli
Endothelin-1 Angiotensin II Endothelin-1 Angiotensin II
Stimulators Angiotensin Endothelin Pulsatile stretch Pulsatile stretch
Insulin Insulin Shear stress (low) (cardiomyocytes)
Cytokines Cytokines Osmolarity Volume depletion
Interleukin-1 Interleukin-1 Hypoxia
Oxidized LDL Oxidized LDL
Vasopressin Progesterone
Adrenalin
TGF-β
Endotoxin
Glucose
Inhibitors Nitric Oxide Nitric oxide Statins Statins
Oestrogens Oestrogens Shear stress (high) Atrial distension
Prostacyclin FGF
Heparin Free radicals
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LDL, low-density lipoprotein; FGF, fibroblast growth factor.

Angiotensin II

After cleavage of angiotensinogen to angiotensin (Ang) I via renin, this peptide is cleaved by the angiotensin converting enzyme (produced by pulmonary and systemic vascular endothelium) into Ang II, which binds to its specific receptors on the vascular wall. Various stimuli alter the level of synthesis of Ang II (Table 1). Two well-described subtypes of the Ang II receptors, designated AT1 and AT2, have been identified. The smooth muscle cell-localized AT1 receptor subtype mediates the predominant action of Ang II: vasoconstriction. These vasoactive actions are partly counteracted by the AT2 receptor, which causes vasodilatation (Hernandez Schulman et al. 2007). Besides the vasoactive effects, Ang II leads to proliferation and growth of the vascular smooth muscle cells through activation of the AT1 receptor.

Thromboxane A2

Thromboxane A2 (TXA2) is one of the end products of arachidonic acid metabolism and is produced by TXA2 synthase. TXA2 is primarily produced by platelets, but also by the endothelium. The physiological role of TXA2 is platelet aggregation and vasoconstriction (Oates et al. 1988).

Prostaglandins

While prostaglandins have vasodilator effects, the prostaglandin H2 (PGH2) isoform is a vasoconstrictor substance. PGH2 is closely related to TXA2: both are formed during arachidonic acid metabolism, and PGH2 is the precursor of TXA2 and exerts its vascular effects through the same receptors on the vascular wall (Davidge, 2001).

We are not aware of any studies that have examined the potential role of TXA2 or PGH2 in cardiovascular changes during physical (in)activity. Therefore, the role of these two endothelium-derived vasoconstricting factors will not be discussed in this review.

Physical inactivity

Functional changes

While 5–18 days of space flight did not alter ET-1 plasma concentrations in humans (Meck et al. 2004), increased ET-1 plasma concentrations were observed after hindlimb unloading in rats (Biondi et al. 1995) and detraining in humans (Maeda et al. 2001). Short-term bed rest increased concentrations of Ang II (Haruna et al. 1997; Bestle et al. 2001). Paralysed muscles of spinal cord-injured individuals are subject to extreme inactivity and can therefore serve as a ‘model of nature’ for localized deconditioning. This population demonstrated high concentrations of ET-1 (Robergs et al. 1993), which increased even further after a period of training. Interpreting these scattered results, one should realize that plasma concentrations do not necessarily indicate a functional change in these pathways. In our lab, we examined ET-1 plasma concentrations and the ET-1-mediated leg vascular tone after intra-arterial blockade of ETA/B receptors using BQ-123 and BQ-788 in the same subjects (Thijssen et al. 2007a,c). Combining the results of these studies, we found that ET-1 plasma concentrations do not correlate with the contribution of ET to baseline vascular tone (Fig. 2). However, baseline leg blood flow and ET-1-mediated vascular tone showed an inverse relation (r2= 0.12, P = 0.03), indicating that a low leg blood flow correlates with an elevated ET-1-mediated vascular tone. This advocates the use of local infusion to assess the role of ET-1 to regulate vascular function, rather than plasma concentrations.

Figure 2. Correlation between the relative change in blood flow of the infused leg during ET blockade (representing the contribution of ET-1 to leg vascular tone) and baseline plasma concentrations of ET-1.

Figure 2

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Recently, we examined the contribution of ET-1 to baseline blood flow in extremely inactive legs of spinal cord-injured (SCI) individuals, using an intrafemoral administration of selective ETA/B receptor blockers (Thijssen et al. 2007a). We demonstrated that ET-1 importantly contributes to the increased vascular tone observed during physical inactivity. This is supported by the reversed ET-1-mediated vascular tone in these subjects after 6 weeks of exercise training.

Regarding Ang II, it was demonstrated that significantly lower dosages are necessary in SCI individuals compared with able-bodied controls to achieve a similar increase in blood pressure (Krum et al. 1992). This suggests the presence of an exaggerated pressor response to Ang II in SCI individuals.

Structural changes

To date, no studies have examined the role of endothelium-derived vasoconstricting factors in the regulation of physical inactivity-induced structural changes, such as an inward remodelling of conduit arteries during inactivity.

Physcial activity as an intervention

Functional changes

Using a cross-sectional design, it was demonstrated that the ET-1-sensitivity, ex vivo examined using the concentration of ET-1 necessary to cause a 50% response (EC50), of the aorta and coronary artery is reduced after a period of exercise training in swine (Jones et al. 1999). In addition, aortic and cerebellar arteries in exercise-trained rats have a diminished sensitivity to the actions of ET-1 on lipid metabolism compared with sedentary rats (Latorre et al. 2002). Moreover, the postischaemic sensitivity to ET-1 in coronary arteries was significantly lower in endurance-trained rats than in sedentary rats (Symons et al. 2000). Regarding the Ang II pathway, an exercise-induced decrease in Ang II-induced pulmonary vasoconstriction was present in rats that trained for 6 weeks (Kashimura et al. 1995). In humans, only one single study examined potential differences in the regulation of vascular tone by Ang II between healthy athletic and sedentary men. A similar response is reported in forearm vascular bed for Ang II (but also for NO), between elite athletic and sedentary healthy men (Kingwell et al. 1996).

Structural changes

Based on their potent proliferative acivity, both ET-1 and Ang II contribute to pathological structural changes. This is supported by the inhibited formation of atherosclerotic lesions during prolonged ETA receptor blockade (Barton et al. 1998) and by the accelerated atherosclerotic process during overexpression of the AT1 receptor (Nickenig & Harrison, 2002). Regarding the effects of exercise, lower ET-1-mediated DNA expression in arteries was found in exercise trained swine compared with sedentary peers (Wamhoff et al. 2002). Because amounts of DNA synthesis are suggested to correlate with proliferative activity (and therefore atherosclerosis), decreased proliferative responses of constrictor pathways may contribute to the exercise-induced cardioprotection. In addition, ET-1 and Ang II are hypothesized to contribute to angiogenesis. Under hypoxic conditions, ET-1 induces angiogenesis via activation of the ETB receptors (Goligorsky et al. 1999) and via enhanced expression of NO synthase (Liu et al. 2003), while Ang II results in angiogenesis through the actions of the vascular endothelial growth factor (Amaral et al. 2001).

Physical activity in specific groups

Ageing

Animal studies demonstrated that ET-1 (possibly through ETA receptors) and Ang II (possibly through AT2 receptors) contribute to the age-related increase in vascular tone in coronary arteries (Goodwin et al. 1999; Korzick et al. 2005), mesenteric vessels (Pinaud et al. 2007), gastrocnemius vascular bed (Donato et al. 2005), total vascular bed (Asai et al. 2001), and renal arteries (Tank et al. 1994). Recently, the pivotal role of ET-1 in the age-related increase in vascular tone was confirmed with human in vivo experiments in the lower (Thijssen et al. 2007c) as well as in the upper extremities (Van Guilder et al. 2007). In the forearm, this was possibly regulated via ETA receptors (Van Guilder et al. 2007). Examining the potential beneficial effects of exercise training in ageing, it was demonstrated that 12 weeks of exercise in old rats did not change ETA/B receptor-mediated responsiveness, examined ex vivo using the EC50 value, of muscle arterioles (Donato et al. 2005). This finding is in contrast with two recent human in vivo studies, which reported a partly reversed ET-1-mediated vascular tone after exercise training in older men in the leg (Thijssen et al. 2007c) and forearm (Van Guilder et al. 2007) vascular bed. Based on these recent findings, it is hypothesized that the negative effects of ET-1 in cardiovascular disease, predominantly occurring in the ageing population, may be due to inactivity rather than to senesence (Thijssen et al. 2007b).

Coronary artery disease

It has been demonstrated that exercise training in patients with stable coronary artery disease leads to a 49% reduction in Ang II-induced vasoconstriction. Moreover, this adaptation is accompanied by lower expression of the AT1 receptor and increased expression of the AT2 receptor (Adams et al. 2005).

Pulmonary hypertension

Only one study so far has examined the vascular effects after 5 weeks of exercise training in pulmonary hypertensive rats on the ET pathway. While the pulmonary vasomotor function improved, the pulmonary vasoreactivity to vasoactive agents (e.g. ET-1) did not change (Goret et al. 2005). Pulmonary hypertension is the only widely accepted cardiovascular pathology that is treated with ET receptor blockers, so a large potential exists for exercise training to attenuate the central and peripheral vasoactive effects of the ET pathway in this disease.

Heart failure

Decreased plasma concentrations of Ang II have been reported after exercise training in rabbits with heart failure (Liu et al. 2000), while the significant up-regulation in AT1 receptor mRNA in heart failure in rats is normalized after exercise training (Zucker et al. 2004). Also in patients with heart failure, improving physical fitness results in suppressing circulating concentrations of Ang II (Braith et al. 1999) and lowering of plasma concentrations of ET-1 (Kubanek et al. 2006).

Conclusions

The studies discussed in the present review suggest that inhibition of endothelium-derived vasoconstricing pathways contribute to exercise-induced vascular changes. Accordingly, cardiovascular adaptations to a change in physical activity are likely to be regulated through tight interactions between vasodilator (e.g. NO) and vasoconstrictor pathways (e.g. ET-1, Ang II). This may even be of special interest in disease states characterized by altered endothelium-derived constrictor pathways. Better insight into the underlying mechanisms (e.g. the role of the receptors and of the post receptor signalling pathways) will help us to understand the vascular changes observed in physical (in)activity. In addition, little is known regarding the role of endothelium-derived vasoconstictors in structural changes after exercise or inactivity. Also the field of vasoconstrictor prostanoids (TXA2 and PGH2) is relatively unexplored.

With respect to cardiovascular diseases, several scientific lines of evidence are present that support a central role for endothelium-derived vasoconstricting factors. Based on the summarized findings in this review, one should realize that the negative effects of ET-1 and Ang II in cardiovascular disease may be importantly confounded by the degree of inactivity. Therefore, inactivity, rather than the pathology of these specific cardiovascular diseases, is emerging as a strong candidate to explain the increased vascular tone. However, only a few studies examined the effect of exercise training on the role of these vasoconstricting factors. The sparse data at present suggest that exercise training potentially improves cardiovascular function in these patients (at least partly) through inhibition of the constrictor pathways. We strongly advocate that future studies should examine the potential for exercise training as a non-pharmacological intervention in cardiovascular diseases, and take particular interest in vasoconstrictor-related mechanisms to explain the possible beneficial cardiovascular effect.

Acknowledgments

We apologize for the failure to cite many important publications because of space limitations. D.H.J.T. is financially supported by the Netherlands Organization for Scientific Research (NWO-grant 82507010).

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