Effects of a single aerobic exercise on perfused boundary region and microvascular perfusion: a field study

Microvascular perfusion is adapted to local needs by fine-tuned adaptive mechanism. In this context, the endothelial glycocalyx and the endothelium play a pivotal role in regulating microvascular function and perfusion. The glycocalyx is composed of proteoglycans and glycosaminoglycans on its luminal site. It is part of the endothelial surface layer (ESL) that contains associated soluble plasma proteins and immobilised plasma. The ESL is involved in many physiological functions such as mechanotransduction, haemostasis, signalling, and blood cell–vessel wall interactions [1, 2]. Given these essential functions, ESL degradation will lead to formation of tissue edema, loss of nutritional blood flow and leucocyte adhesion in states of critical illness such as sepsis, ischaemia–reperfusion-injury and trauma [2]. Experimental models of ischaemia/reperfusion and hypoxia/reoxygenation showed that myocardial hypoxia and ischaemia induce an early ESL degradation [3], with purin signalling and perivascular mast cell-derived heparanase being a possible contributing factor [4]. Increased blood levels of shed ESL components such as syndecan-1, hyaluronan and heparan sulphate can be detected in successful cardiopulmonary resuscitation after cardiac arrest, trauma and sepsis and may serve as an early predictor of adverse clinical outcome [5‐7]. Soluble components of the endothelial glycocalyx may act as damage associated molecular patterns (DAMPs), further augmenting inflammation and tissue damage. Therefore, eliminating these substances from the circulation is under evaluation as a therapeutic intervention [8].

In order to visualise and calculate ESL dimensions, novel non-invasive techniques are available to study the microcirculation in regions that are easily accessible. Recently, clinical studies using intravital microscopy of the sublingual microvasculature have been conducted to assess the ESL in various medical conditions and critical care states [9‐14]. These measurements were performed in patients and controls either in-hospital or in a laboratory setting.

However, rapid changes of ESL dimensions may occur. To this date, it is unknown whether aerobic exercise immediately affects dimensions of the endothelial surface layer and hereby adapts local tissue perfusion. The current study aimed to investigate the microvascular function of healthy adults using the above mentioned non-invasive techniques before and after running a 10 km trial distance. We hypothesised that aerobic exercise will induce a physiological change of ESL dimensions in order to facilitate efficient perfusion. Furthermore, we tested the feasibility of post-exercise on-site measurements to elucidate alternative scenarios for intravital microscopy other than an in-hospital or a laboratory setting.

We were not able to detect an immediate effect on ESL dimensions following aerobic exercise in this study. There was a negative association of PBR and RBC filling percentage at baseline, as has been described in previous studies [9, 15, 16]. This negative association of PBR and RBC filling percentage was maintained and even more pronounced after aerobic exercise, resulting also in a distinct association between change of PBR and change of RBC filling percentage. This aerobic exercise-stimulated association between the decrease of PBR and an increase of RBC filling percentage suggests that the endothelium and its ESL facilitate beneficial conditions for efficient perfusion in a hyperdynamic state like aerobic exercise.

In a previously published study, healthy volunteers performed an all-out running high-intensity interval training with one weekly session for four weeks [19]. Maximal exercise performance capacity (as measured by an incremental continuous running test) and PBR showed a negative correlation at baseline. The change in exercise performance capacity and the change in PBR showed an intensified negative correlation after the intervention indicating greater ESL thickness with improved exercise performance capacity [19]. It is intriguing to speculate that repeated endurance or high-intensity interval training might have a protective effect on the microvasculature as we did not find an immediate effect of a single aerobic-exercise on ESL dimension in our study. The underlying mechanisms have yet to be elucidated. A possible mechanism being discussed is an enhanced resistance of the ESL following repeated training sessions. For instance, moderate-intensity endurance training four times a week for 20 weeks performed by untrained young men lead to reduced syndecan-1 and heparan sulphate levels at rest and lower levels of these ESL degradation parameters after an incremental cycling test until exhaustion following the intervention [20]. Interestingly, maximal incremental cycling until exhaustion in 21 untrained men (mean age: 23 years) did not affect syndecan-1 and heparan sulphate levels [21] as opposed to an acute bicycle test with 45 min at an intensity of 70% of individual maximum oxygen uptake performed in individuals with a mean age of 50 yrs that led to an increase in levels of syndecan-1 and syndecan-4 [22]. Aging appears to be a factor contributing to ESL integrity. Lee et al. conclude that increased blood flow causes ESL degradation [22]. As we did not measure ESL shedding parameters, we do not know whether the preserved ESL dimensions were accompanied by stable levels of ESL shedding parameters or not. In addition, we did not assess maximum performance capacity before and after an intervention but were interested in the effect of a onetime aerobic-exercise on PBR. Hence, we cannot offer data regarding the association of individual performance capacity and PBR. Running time and PBR did not show a significant relation (data not shown). Neither valid nor total capillary density, nor the ratio of valid to total capillary density did change post-exercise. Hence, immediate capillary recruitment after a single aerobic-exercise was not detectable in our study but might be present when exercise is performed regularly or when measured in athletes. Patients with chronic heart failure have a lower valid and total capillary density, but a higher ratio of valid to total capillary density [23]. It suggests perfused capillary recruitment in an otherwise rarefied microcirculation. This increased ratio is also seen with age, body-mass-index, total cholesterol, and Framingham risk score [24] and may indicate a chronic adaptation process.

This was the first field study to assess the effect of aerobic exercise on ESL dimensions. ESL reactions of the sublingual mucosa may differ from tissues with high oxygen demand as heart and skeletal muscle in such scenarios. Participants older of age, concomitant arterial hypertension, dyslipidaemia or dysglycaemia may show other endothelial reactivity and tissue perfusion compared to the healthy volunteers we studied. As we did not conduct invasive measurements, we were not able to assess lactate levels.

We report the feasibility of an alternative scenario for intravital microscopy with automised analyses other than an in-hospital or a laboratory setting. We conclude that the endothelium of the microvasculature facilitates efficient perfusion in vessels reacting with an increased endothelial surface layer.