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The Effect of Age-Related Endothelial Dysfunction on Exercise Blood Flow

By Abigail Dorff

Figure 1: Summary Figure – Diminished vascular health may contribute to exercise intolerance with age

Introduction  

With aging everyday things like walking through the grocery store become difficult. This difficulty can be a result of endothelial dysfunction. Endothelial dysfunction can also cause major issues like heart attack or stroke. While being active can blunt endothelial dysfunction, it will still occur as you age. The following studies will show that vascular function decreases as we age, resulting in impaired sympatholysis and decreased functionality.

What Is the Vascular Endothelium?

The vascular endothelium is the innermost layer of the vasculature. This layer is a semipermeable barrier that regulates fluid, nutrients, and metabolite movement from the blood to the necessary organ1. The middle, or the tunica media (Figure 2), consists of smooth muscle tissue. This regulates vasodilation and vasoconstriction of the artery. With aging, vascular health decreases, causing impaired blood flow which can result in major issues such as hypertension, cardiac arrest, or even death. The purpose of this review is to summarize the impact of aging on the vasodilatory function of the vascular endothelium.

While decreased vascular health can be the result of many causes, the result of each cause is damage to the endothelial layer of the artery. Hypertension, for example, increases the stress on the artery walls because the lumen, the area that the blood passes through, has decreased but the blood volume remains the same resulting in more pressure pushing against the artery wall ultimately, damaging the endothelium1. Damaged endothelium decreases the artery’s ability to vasodilate resulting in decreased blood flow. The lack of vasodilation, or inhibited sympatholysis, becomes dangerous1.

Figure 2 The layers of an artery.

Endothelial Dysfunction and Sympatholysis During Exercise

During exercise, the arteries in the working muscle dilate, via a process called sympatholysis, in the face of a systemic signal to constrict all muscle arteries2 (Figure 3). Sympatholysis is primarily controlled by the endothelium of the vasculature, which releases factors like Nitric Oxide (NO-) and Prostacyclin to cause localized vasodilation in the face of systemic vasoconstrictor signals2. Since vasoconstriction occurs by default in skeletal muscle during exercise, blood flow and oxygen delivery will not increase sufficiently if endothelium-dependent dilation is impaired3. Endothelium-dependent dilation and muscle blood flow are impaired with aging4,5. Hydren et al.,6 demonstrated that the release of NO- and subsequent hyperemia in response to passive exercise is impaired in older adults. Likewise, Gliemann et al.7 showed that endothelial responsiveness is impaired by aging in women, even when physically active.

Figure 3 Sympatholysis. First, the artery at rest. Second, the artery constricts because the sympathetic nervous system releases norepinephrine. Third, EDDs (endothelial dependant dilators) cause vasodilation.

During exercise, the sympathetic nervous system predominantly signals for vasoconstriction throughout the body to reduce blood flow to inactive areas10. Simultaneously, metabolite buildup occurs from glycolysis in the exercising muscle stimulating the endothelium to release EDDs (endothelial-dependent dilators) like Nitric Oxide (NO-)10,3. If the stimulus is great enough, the vasodilator signal from NO- can locally outweigh the vasoconstrictor signal of the sympathetic nervous system10,3. This local outweighing of the sympathetic signal allows the artery to increase in diameter and allows for more blood to travel through the arteries that are dilated therefore more oxygen gets to the working muscles10. Clearly, the ability of the arteries to produce vasodilators like NO- and subsequently to dilate, can strongly influence the delivery of blood to active muscle during exercise.

Sympatholysis allows the body to control the distribution of blood11. During exercise, this is important because the working muscle needs more blood. The sympathetic nervous system causes vasoconstriction increasing blood pressure. With less vasodilation, blood pressure can rise to a harmful level. As well as damaging the vasculature, this reduces the delivery of blood to the exercising muscle, resulting in exercise intolerance. With inefficient functional sympatholysis, maldistribution to the working muscle is seen. Maldistribution is an insufficient distribution of the blood to the exercising muscle, resulting in decreased oxygen availability in the exercising muscle11. Decreased muscle blood flow is linked with lower oxygen availability and results in quicker fatigue because of a reliance on anaerobic ATP resynthesis. Because the heart is an aerobically based muscle, lack of blood flow can result in a heart attack or damage to the heart tissue. In sedentary older men, sympatholysis and muscle blood flow are impaired when compared to young men. Functional sympatholysis is essential for sustainable exercise like walking. Vascular function assessed by PLM has been shown to decrease in older adults. Indeed, Groot et al. demonstrated that the hyperemic response to passive leg movement decreases with aging and that physical activity throughout aging can prevent part, but not all, of the decreases in vascular function12. Hydren et al. recently showed that the decrease in vascular function can also be observed with the single passive leg movement technique6.

The Research

Mortensen et al.8 found that impaired sympatholysis leads to attenuated blood flow through the femoral artery during knee extension exercise in sedentary older adults, but not physically active older adults. Unfortunately, no comparison was made between young physically active and old physically active subjects. Not all studies agree, but submaximal blood flow could be down by 10-15% with aging9. In young, healthy individuals, exercise simultaneously stimulates two processes – systemic sympathetic activity and local sympatholysis.

Vascular Function in Active and Sedentary Adults

In a study by Mortensen et al. vascular function was determined by the blood flow response to knee extension exercise measured in young and old sedentary and old active adults8. Leg blood flow and VO2 were blunted in sedentary adults, but not active adults8. Moreover, the sedentary old group had an impaired ability to offset a signal for vasoconstriction during exercise8. Together these data indicate that sedentary aging is associated with a diminished ability of functional sympatholysis, which is related to impaired endothelial function8. This indicates that physical activity may influence everyday functional declines.

Mortensen et al. 8

Gliemann et al. studied vascular function in postmenopausal women7. The women were separated into inactive, moderately active, and very active groups7. Vascular function was assessed by ultrasound Doppler of the femoral artery during infusion of acetylcholine (Ach)7. It was determined that the very active group was 76% more responsive to Ach and had 200% more prostacyclin (an endothelium-derived vasodilator) than the sedentary group7. This indicates that activity level affects vascular function. They also compared the very active group with a smaller group of young habitually active young women7. This comparison showed that smooth muscle responsiveness and endothelial responsiveness are affected by aging7. This responsiveness indicates that vascular function decreases with aging, which could impair functional sympatholysis and exercise tolerance.

Relationship Between Blood Flow and Vasodilation

In a study by Munch et al., functional sympatholysis in heat failure patients and in healthy individuals were looked at during 6 weeks of high-intensity one-legged cycling13. While there was no difference between the groups when injected with acetylcholine and sodium nitroprusside, which induce vasodilation, the peak vasodilatory response to ATP was blunted in the heart failure group13. This study shows that a decrease in blood flow (heart failure group) results in reduced peak vasodilatory responses.

What’s Next

While we know that endothelial function decreases with aging and that exercise can help increase endothelial health, we do not yet know if specific types of exercise has the biggest effect on endothelial health. Any exercise is going to better than no exercise but will high intensity aerobic exercise have a greater impact on endothelial health than moderate intensity aerobic exercise or aerobic exercise compared to resistance exercise.

Conclusion

Ultimately, these studies conclude that with aging, vascular function decreases, which can result in impaired sympatholysis and decreased functionality. While being active in old age can help blunt the decrease in vascular function, it will still decrease with age. A decrease in vascular function is important because it can result in dangerous situations like a heart attack or stroke, but it can also make everyday activities like walking through the grocery store difficult and strenuous.

Bibliography:

1.        Alexander Y, Osto E, Schmidt-Trucksäss A, et al. Endothelial function in cardiovascular medicine: A consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis. Cardiovascular Research. 2021;117(1):29-42. doi:10.1093/cvr/cvaa085

2.        Remensnyder JP, Mitchell JH, Sarnoff SJ. Functional sympatholysis during muscular activity. Circ Res. 1962;11:370-380. doi:10.1161/01.RES.11.3.370

3.        Quyyumi AA. Endothelial function in health and disease: New insights into the genesis of cardiovascular disease. American Journal of Medicine. 1998;105(1 A):32S-39S. doi:10.1016/s0002-9343(98)00209-5

4.        Donato AJ, Gano LB, Eskurza I, et al. Vascular endothelial dysfunction with aging : endothelin-1 and endothelial nitric oxide synthase. American Journal of Physiology-Heart and Circulatory Physiology. 2008;297:H425-H432. doi:10.1152/ajpheart.00689.2008

5.        Behnke BJ, Ramsey MW, Stabley JN, et al. Effects of aging and exercise training on skeletal muscle blood flow and resistance artery morphology Effects of aging and exercise training on skeletal muscle blood flow and resistance artery morphology. 2012;(October):1699-1708. doi:10.1152/japplphysiol.01025.2012

6.        Hydren JR, Broxterman RM, Trinity JD, et al. Delineating the age-related attenuation of vascular function: Evidence supporting the efficacy of the single passive leg movement as a screening tool. Journal of Applied Physiology. 2019;126(6):1525-1532. doi:10.1152/japplphysiol.01084.2018

7.        Gliemann L, Rytter N, Tamariz-Ellemann A, et al. Lifelong Physical Activity Determines Vascular Function in Late Postmenopausal Women. Medicine and Science in Sports and Exercise. 2020;52(3):627-636. doi:10.1249/MSS.0000000000002180

8.        Mortensen SP, Nyberg M, Winding K, Saltin B. Lifelong physical activity preserves functional sympatholysis and purinergic signalling in the ageing human leg. Journal of Physiology. 2012;590(23):6227-6236. doi:10.1113/jphysiol.2012.240093

9.        Koch DW, Newcomer SC, Proctor DN. Blood_flow_to_exercising_limbs. Accessed April 6, 2022. https://pubmed.ncbi.nlm.nih.gov/16293904/

10.      Remensnyder JP, Mitchell JH, Sarnoff SJ. Functional sympatholysis during muscular activity. Circulation research. 1962;11:370-380. doi:10.1161/01.RES.11.3.370

11.      Poole DC, Behnke BJ, Musch TI. The role of vascular function on exercise capacity in health and disease. Journal of Physiology. 2021;599(3):889-910. doi:10.1113/JP278931

12.      Groot HJ, Rossman MJ, Garten RS, et al. The Effect of Physical Activity on Passive Leg Movement-Induced Vasodilation with Age. Physiol Behav. 2016;48(8):1548-1557. doi:10.1249/MSS.0000000000000936.

13.      Munch GW, Iepsen UW, Ryrsø CK, Rosenmeier JB, Pedersen BK, Mortensen SP. Effect of 6 wk of high-intensity one-legged cycling on functional sympatholysis and ATP signaling in patients with heart failure. American Journal of Physiology – Heart and Circulatory Physiology. 2018;314(3):H616-H626. doi:10.1152/ajpheart.00379.2017

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