CrossTalk proposal: Acute exercise elicits damage to the endothelial layer of systemic blood vessels in healthy individuals

There is no doubt that exercise training has a beneficial effect on the vasculature in healthy individuals and patients with cardiovascular disease via various molecular mechanisms, i.e. reduction of oxidative stress and inflammation, and activation of endothelial nitric oxide synthase (eNOS) (reviewed in Adams et al. 2017). Based on the preconditioning hypothesis, it is speculated that repeated stimuli (e.g. bouts of exercise), temporarily impairing the system, provide the foundation for prolonged adaptation (improvement in endothelial function) to exercise. Following this hypothesis one would argue that a single bout of exercise leads to an impairment of endothelial function due to damage to the endothelial layer. Do we have evidence that acute exercise elicits some damage to the endothelial cell layer? Examining endothelial function by measuring flow-mediated vasodilatation (FMD) in the brachial artery in healthy subjects before and after performing acute exercise, some (Dawson et al. 2008; Rognmo et al. 2008; Gonzales et al. 2010; Hwang et al. 2012; Johnson et al. 2012; Llewellyn et al. 2012; Birk et al. 2013; Mills et al. 2013) but not all (Cosio-Lima et al. 2006; Harris et al. 2008; Zhu et al. 2010; Hallmark et al. 2014) researchers reported a significant reduction in FMD. An important factor related to the reduction in FMD is exercise intensity, duration and timing of FMD measurement. In a study performed by Birk and colleagues (2013), change in FMD was only seen in individuals exercising for 30 min at 70 or 85% of maximal heart rate, whereas when cycling for 30 min at 50% of maximal heart rate no change in FMD was detected. Of note, FMD returned to baseline values by 1 h post-exercise. This intensity-dependent impairment of FMD was confirmed by a study of Johnson et al. (2012). The reduction in endothelial function by exercise even seems to be independent of changes in shear rate as documented by Llewellyn and colleagues (2012). So what are the potential molecular explanations for the impairment of endothelial function? To answer this question it is important to search for factors influencing endothelial cell function since the endothelium-independent vasodilatation is not altered by an acute bout of exercise (Llewellyn et al. 2012). Definitively the balance of vasoconstrictive (e.g. endothelin-1; ET-1) and vasodilatory agents (nitric oxide) will determine the vascular response. With respect to ET-1, cycling for 30 min at 130% of the individual ventilator threshold increased plasma concentration of ET-1 (Maeda et al. 1994) for up to 30 min after the exercise stimulus. Of importance, this increase was again dependent of the exercise intensity and was blunted 1 h after performing the test. With respect to the exercise-induced changes in NO, the data are less clear. Experimental data obtained in mouse/rat aorta (Barbosa et al. 2013; Tanaka et al. 2015) or microvessels (Cocks et al. 2012) documented that 'acute' exercise at moderate intensity (55–60% for 1 h) (Tanaka et al. 2015) or 3 h swimming (Barbosa et al. 2013) enhanced NO bioavailability. Unfortunately, as mentioned above, the intensity may not be high enough and the time from exercise to tissue harvesting too long. Another factor influencing NO bioavailability is the amount of reactive oxygen species (ROS). Measuring the concentration of thiobarbituric acid reactive substances as a marker for ROS, 30 min of exercise, independent of intensity, resulted in an elevation of this marker. This increase was not evident when performing an exercise for 1 h and interestingly the elevation observed immediately after the test was blunted 1 h post-exercise. Taken together, one can postulate that endothelial dysfunction (measured as decrease in FMD) occurs but only if the exercise intensity is high enough (>70% ) and the duration of the exercise bout is short enough (< 1 h). At the molecular site this temporary endothelial dysfunction is mediated by an increase of vasoconstrictors and possibly an increase in ROS. Unfortunately most measurements were made in conduit vessels (brachial artery or aorta) and therefore data on microvessels and even veins are scarce and more information is needed. Is the measurement of FMD an ideal marker for quantifying endothelial damage, since it is influenced by many factors as discussed above? If FMD does not reflect endothelial damage only, what markers would be suitable to indicate endothelial cell damage by acute exercise? The detection of liberated molecules primarily expressed in endothelial cells or remnants of endothelial cells in the circulation may be more suitable as a marker for endothelial damage. As summarized in Table 1, several molecules (von Willebrand factor, thrombomodulin, microRNAs), cell fragments (endothelial microparticles), or even intact cells are reported to indicate cell destruction (circulating endothelial cells) or increased cell repair (endothelial progenitor cells). The benefit of measuring these markers for endothelial damage may also be that they can be assessed easily in blood taken from the patient or even in blood stored at −80°C. Taken together, based on the data presented it is reasonable to assume that an acute bout of exercise at a high enough intensity damages the endothelial cells in systemic blood vessels (most data are available for conduit vessels). This can be documented by either measuring a decrease in FMD or quantifying circulating markers indicative for endothelial cell damage. This endothelial damage is only detectable for a short time before it is repaired by cellular mechanisms such as endothelial progenitor cells. We even may postulate that this initial temporally limited damaging step is important to initiate the physiological benefit of exercise training with respect to endothelial function. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief (250 word) comment. Comments may be submitted up to 6 weeks after publication of the article, at which point the discussion will close and the CrossTalk authors will be invited to submit a 'LastWord' Please email your comment, including a title and a declaration of interest, to jphysiol@physoc.org. Comments will be moderated and accepted comments will be published online only as 'supporting information' to the original debate articles once discussion has closed. Volker Adams obtained his PhD in Biology at the University of Konstanz, focusing on isolation and characterization of mitochondrial contact sites in different organs. His postdoctoral training was in molecular genetics at the Institute of Molecular Genetics, Baylor College of Medicine, Houston, TX, USA. After moving to Leipzig and taking the position of head of the research laboratory at the Heart Centre Leipzig, his main research interest during the past 20 years has been to understand the molecular changes in the endothelium and skeletal muscle related to the beneficial effects of exercise training. In December 2017 he moved to Dresden and took the poistion as head of the research laboratory of the department of Cardiology at the TU Dresden. Disclaimer: Supporting information has been peer-reviewed but not copyedited. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared.