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Effect of Heat on Endothelial Function

This review highlights the effects of heat, specifically passive heating on vascular function. Thermoregulatory responses to heat increase vascular shear stress, a potent stimulator for endothelium-derived dilators, specifically nitric oxide.

Section 1: Background Physiology

What is endothelial function?

The interior lining of human vasculature consists of a single layer of endothelial cells. This endothelial layer plays an important role in the maintenance of vascular function. Vascular function is necessary for the appropriate distribution of blood flow. As illustrated by Poiseuille’s law below, changes in radius will have the greatest impact on blood flow. Changes in radius and consequently flow are the result of a coordinated input of signals from the sympathetic nervous system to vasoconstrict, and signals from the vascular endothelium to dilate(1).

Poiseuille’s law calculates the changes in flow by dividing the product of the change in pressure (delta P), pi, and the radius (r) by the product of 8, the viscosity of the blood (n), and the length of the artery (l). During endurance exercise, the change in pressure and the radius are the primary components that will affect flow. Since the radius is raised to the fourth power, any change in radius will have the greatest impact on flow.

During exercise, increases in sympathetic activity result in systemic vasoconstriction. Blood flow to active muscles during exercise is dependent on the release of factors such as nitric oxide (NO) from the endothelium. NO released from the endothelium of active muscles acts on vascular smooth muscle, resulting in dilation (2, 3). Therefore, proper vascular function is essential for allocation of blood flow during exercise and vascular function is dependent on an intact, functioning endothelium(1).

Single-layer of endothelial cells.

Effect of shear stress on endothelial function?

A potent signal for NO release from the endothelium is shear stress. Shear stress is the frictional force exerted by the blood on the vessel wall(4, 5) and can be calculated using the equation below.

Shear Stress = Blood Viscosity x Blood Velocity / Internal Diameter

Exercise is associated with an increase in shear stress. This increase in shear stress is observed in larger conduit and resistance arteries as the production of metabolic byproducts increases in working muscles. These metabolites result in dilation of downstream arterioles (3, 6). As arterioles dilate, blood flow through downstream capillaries and postcapillary venules increases to provide enhanced nutrient delivery and removal of waste products from working muscles (6, 7). This increase in blood flow through arterioles must be matched by an increase in blood flow through the upstream conduit and resistance arteries. This enhances the flow gradient in the arterial system and results in an increase in flow velocity through upstream vasculature. As velocity increases, shear stress on the endothelium increases resulting in NO release from the endothelium (3, 4, 8).

How does blood flow respond to heat?

Exposure to heat results in a rise in core temperature. With core temperature in humans being tightly regulated, small deviations in internal temperature signal the preoptic area of the hypothalamus (9) to initiate thermoregulatory responses. If core temperature reaches 40C or higher tissue damage and heatstroke can occur (10).  

To dissipate heat, peripheral and cutaneous blood flow increases following an increase in core temperature. At temperatures above 34C, the primary mechanism for heat loss will be evaporative heat loss or sweating. As blood flow to the skin increases(11), the resultant increase in pressure in cutaneous vascular beds causes fluid shifts to extracellular space and eventually taken into the sweat glands to be secreted (12). The evaporation of sweat from the skin surface results in heat transfer to the environment and consequently cooling of the skin.

Blood flow to the skin and sweat gland proximity.

This increase in skin blood flow is the result of dilation in cutaneous vascular beds. As peripheral vasculature volume increases, the velocity at which blood passes through upstream arteries is increased, resulting in an increase in shear stress on upstream arteries (14). Like exercise, the increased velocity produces a shear stress on the endothelium of upstream larger arteries, increasing NO production from the endothelium (5, 17).

Section 2: Vascular Function Responses to Passive Heat

If thermoregulatory mechanisms result in an increase in skin blood flow and consequently increases in arterial shear stress, the question arises of whether passive heat treatment could be utilized to elicit similar vascular adaptations seen with exercise. Passive heat treatment has been shown to increase vascular function. Various approaches have been taken to determine the effects of passive heat treatment on vascular function with heat treatment being administered using short wave diathermy, hot water immersion, water perfused suits, as well as heat chambers or saunas.

Brunt 2016 (13) showed that passive heat therapy improves cutaneous microvascular function in sedentary humans via improved nitric oxide-dependent dilation. These improvements in function were assumed in large part to the increase in shear stress associated with heat exposure.

Passive heat treatment has also been shown to improve vascular function in older adults. Romero et al., 2017 (15) showed that shear stress increases in both young and old individuals following passive heat treatment through hot water immersion. While shear rate was significantly increased in both the older and younger individuals, Romero reported that only the old subjects saw an increase in macro and microvascular function. These findings suggest a potential therapeutic role of chronic passive heating to improve vascular health.

This video illustrates how vascular function is assessed through flow-mediated dilation or FMD. An artery is visualized, and flow is measured. Following a minute of baseline measurements, the artery is occluded using a blood pressure cuff. After the five minutes, the cuff is released and the increase in blood flow following the release is recorded.

A study done by Thomas et al., 2017(16) assessed acute responses to lower limb passive heat using hot-water immersion in patients with peripheral arterial disease. A single bout of lower limb produced significant increases in shear rate and lower limb blood flow in elderly subjects with and without peripheral artery disease.

The key findings represented by these studies are that (i) passive heating results in an increase in artery shear stress. Increased artery shear stress is known to be a potent stimulator of NO release from the endothelium. The ability of the endothelium to release NO in the presence of sympathetic stimuli is indicative of endothelial function, which is essential for proper blood flow distribution. (ii) The positive effects of passive heating are observed in both young individuals and older. Given that age is associated with a decrease in vascular function (more in previous post), passive heating presents itself as a promising mechanism to prevent further decline in vascular function. (iii) Passive heating results in increased shear stress, resulting in increased vascular function in individuals presenting with vascular disease, specifically peripheral arterial disease. Not only is passive heating effective on healthy arteries, but it also elicits a response in disease states. This suggests that passive heat treatment could be utilized for more than just preventative measures. Individuals with peripheral arterial disease often have limited capacity for exercise because of pain associated with claudication (plaque buildup in arteries of the lower extremities). Heat treatment could be used to stimulate the endothelium in these individuals because it increases shear rate independent of exercise.

Conclusion:

Vascular function is dependent on the health of the endothelium. Functional endothelium releases NO, allowing for dilation in the affected artery. Shear stress has been shown to be an important stimulus for the release of NO. Existing data suggest heat treatment to be a valid method of improving vascular endothelial health.

References

1.        Pohl U, Holtz J, Busse R, Bassenge E. Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension 8: 37–44, 1986. doi: 10.1161/01.HYP.8.1.37.

2.        Gliemann L, Carter H. Sympatholysis: the more we learn, the less we know. The Journal of Physiology 596: 963, 2018. doi: 10.1113/JP275513.

3.        Korthuis RJ. Regulation of Vascular Tone in Skeletal Muscle [Online]. https://www.ncbi.nlm.nih.gov/books/NBK57142/ [22 Dec. 2021].

4.        Roux E, Bougaran P, Dufourcq P, Couffinhal T. Fluid Shear Stress Sensing by the Endothelial Layer. Frontiers in Physiology 11: 861, 2020. doi: 10.3389/FPHYS.2020.00861/BIBTEX.

5.        Green DJ, Hopman MTE, Padilla J, Laughlin MH, Thijssen DHJ. Vascular Adaptation to Exercise in Humans: Role of Hemodynamic Stimuli. Physiological Reviews 97: 495, 2017. doi: 10.1152/PHYSREV.00014.2016.

6.        Sarelius I, Pohl U. Control of muscle blood flow during exercise: local factors and integrative mechanisms. Acta Physiol (Oxf) 199: 349, 2010. doi: 10.1111/J.1748-1716.2010.02129.X.

7.        Clifford PS, Hellsten Y. Vasodilatory mechanisms in contracting skeletal muscle. J Appl Physiol (1985) 97: 393–403, 2004. doi: 10.1152/JAPPLPHYSIOL.00179.2004.

8.        Hellsten Y, Nyberg M, Jensen LG, Mortensen SP. Vasodilator interactions in skeletal muscle blood flow regulation. J Physiol 590: 6297–6305, 2012. doi: 10.1113/JPHYSIOL.2012.240762.

9.        Rothhaas R, Chung S. Role of the Preoptic Area in Sleep and Thermoregulation. Frontiers in Neuroscience 15: 750, 2021. doi: 10.3389/FNINS.2021.664781/BIBTEX.

10.      Yousef H, Ahangar ER, Varacallo M. Physiology, Thermal Regulation [Online]. https://www.ncbi.nlm.nih.gov/books/NBK499843/ [10 Apr. 2022].

11.      Cheng JL, MacDonald MJ. Effect of heat stress on vascular outcomes in humans. Journal of Applied Physiology 126: 771, 2019. doi: 10.1152/JAPPLPHYSIOL.00682.2018.

12.      Baker LB. Physiology of sweat gland function: The roles of sweating and sweat composition in human health. Temperature: Multidisciplinary Biomedical Journal 6: 211, 2019. doi: 10.1080/23328940.2019.1632145.

13.      VE B, TM E, MA F, MJ H, CT M. Passive heat therapy improves cutaneous microvascular function in sedentary humans via improved nitric oxide-dependent dilation. J Appl Physiol (1985) 121: 716–723, 2016. doi: 10.1152/JAPPLPHYSIOL.00424.2016.

14.      Tinken TM, Thijssen DHJ, Hopkins N, Black MA, Dawson EA, Minson CT, Newcomer SC, Laughlin MH, Cable NT, Green DJ. Impact of shear rate modulation on vascular function in humans. Hypertension 54: 278, 2009. doi: 10.1161/HYPERTENSIONAHA.109.134361.

15.      Romero SA, Gagnon D, Adams AN, Cramer MN, Kouda K, Crandall CG. Acute limb heating improves macro-and microvascular dilator function in the leg of aged humans. American Journal of Physiology – Heart and Circulatory Physiology 312: H89–H97, 2017. doi: 10.1152/AJPHEART.00519.2016/ASSET/IMAGES/LARGE/ZH40011721290005.JPEG.

16.      Thomas KN, van Rij AM, Lucas SJE, Cotter JD. Lower-limb hot-water immersion acutely induces beneficial hemodynamic and cardiovascular responses in peripheral arterial disease and healthy, elderly controls. American Journal of Physiology – Regulatory Integrative and Comparative Physiology 312: R281–R291, 2017. doi: 10.1152/AJPREGU.00404.2016/ASSET/IMAGES/LARGE/ZH60021792030005.JPEG.

17.      Amin SB, Hansen AB, Mugele H, Willmer F, Gross F, Reimeir B, Cornwell WK, Simpson LL, Moore JP, Romero SA, Lawley JS. Whole body passive heating versus dynamic lower body exercise: a comparison of peripheral hemodynamic profiles. https://doi.org/101152/japplphysiol002912020 130: 160–171, 2021. doi: 10.1152/JAPPLPHYSIOL.00291.2020.

Illustrations credit: BioRender

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