Divyan Bavan
Introduction
The body relies on the heart to pump blood throughout the body. To deliver this blood, it uses a network of vessels. The driving force for this distribution is blood pressure. While the heart is responsible for generating enough pressure for this process, the vessels are able to regulate it. This is important for tissue-specific blood distribution. Each organ has different metabolic requirements, and thus, requires a different share of the body’s blood supply. If these metabolic requirements change, the blood vessels must adapt to these new conditions. Arterioles—the main resistance vessels of the cardiovascular system—are the main target for these adaptations. They can be controlled intrinsically or extrinsically. The former uses mechanisms such as myogenic, metabolic, and local regulation; the latter uses hormonal, neuronal, and baroreflex regulation. Together, these mechanisms can contribute to the control of tissue perfusion and arterial blood pressure, adapting it for various situations.
Intrinsic Mechanisms: Myogenic Autoregulation
Maintaining a basal level of flow throughout the cardiovascular system is the role of myogenic autoregulation. With the exceptions of pulmonary and cutaneous vessels, all arterioles in the body are myogenically autoregulated. This process is important as changes in arterial blood pressure could affect important vessels in the brain and other areas of the body. Myogenic autoregulation ensures that changes in arterial blood pressure (ABP) do not affect the overall flow through a tissue (Herring and Paterson, 2018).
This mechanism, also referred to as the Bayliss effect, is controlled by stretch-activated cation channels in the smooth muscle. According to Laplace’s law, if the ABP is increased the tension in the vessel wall is also increased. Tension leads to the opening of TRP cation channels, volume-regulated Cl- channels, and epithelial Na+ channels. The effect of these channels is depolarization of the myocytes, which in turn activates voltage-gated calcium channels. Calcium ions can then bind to calmodulin, which activates myosin light chain kinase (MLCK). This causes contraction of the smooth muscle. The result of contraction is vasoconstriction, reducing the radius and bringing flow back to baseline. In the case of a fall in ABP, TRP channels are closed, and less calcium enters the myocytes. This causes relaxation and subsequent vasodilation (Herring and Paterson, 2018).
Several experiments demonstrate the importance of specific ion channels for the Bayliss effect. These experiments involve increasing ABP by raising a reservoir of blood, thus increasing pressure. The normal response can be recorded by measuring flow through the arteriole being studied. By adding various drugs, the importance of specific channels can be investigated. For example, adding gadolinium impairs the response due to its role as a TRP channel blocker. Verapamil also impairs the response, as it is a voltage-gated calcium channel blocker. The response is thus dependent on these channels. If the rise in pressure is sustained, however, mechanisms such as calcium sensitization activate prolonged contraction. This is primarily controlled by RhoA and protein kinase C (Herring and Paterson, 2018).
Intrinsic Control: Metabolic Hyperaemia
While keeping blood flow stable is necessary in many situations, certain tissues require more blood than others. Furthermore, this distribution is dynamic; skeletal muscle, for example, requires a greater proportion of blood during exercise than at rest. For this reason, blood flow can be controlled by the activity of the tissue surrounding it. This is controlled by many factors. These include, but are not limited to, interstitial K+, pH, and adenosine (Herring and Paterson, 2018).
Interstitial K+ is an important determinant of blood perfusion in skeletal muscle. When these tissues are more active, such as in exercise, there is an increased frequency of action potentials. This leads to a build-up of potassium in the interstitial space, as the sodium-potassium pump is unable to restore the original concentrations in time. The increased K+ concentration—going from 4mM to 9mM—leads to activation of hyperpolarizing pumps in smooth muscle. These pumps increase Kir channel activation, further hyperpolarizing the cell. The result of this is relaxation and vasodilation. As expected, this increases blood flow to the skeletal muscle. This is important for meeting the oxygen requirements of the active muscle tissue (Herring and Paterson, 2018).
Cerebral tissue uses a different mechanism to increase flow. When lots of energy is being used, CO2 partial pressure increases; this lowers the pH as CO2 forms HCO3- and H+ ions. This causes hyperpolarization through several mechanisms. For example, a decrease in pH causes the opening of KATP channels. This causes hyperpolarization, closing voltage-gated calcium channels; the result is vasodilation, increasing blood flow (Herring and Paterson, 2018).
Finally, adenosine is critical for increasing blood flow to the heart when it is more active. This chemical is produced through the dephosphorylation of AMP by AMP 5’-nucleotidase. Since AMP is a product of ATP usage, increased cardiac activity leads to an increase in adenosine concentration. Adenosine mainly binds to two types of receptors: A2A and A1 receptors. The former activates adenylyl cyclase and leads to an increase in cAMP. This activates protein kinase A, which phosphorylates MLCK. This decreases its activity and induces vasodilation. A1 receptors use a different mechanism; they are coupled to KATP channels, which cause hyperpolarization when activated. As mentioned previously, this inhibits voltage-gated calcium channels and causes relaxation (Herring and Paterson, 2018; Klabunde, 2021).
Intrinsic Control: Endothelium and Autocoids
Blood flow can be controlled by several paracrine factors. These can be grouped into chemicals released by endothelial cells and autocoids. The former includes ET, NO, EDH, and PGI2; the latter includes histamine, bradykinin, serotonin, and prostaglandins. These chemicals can either be vasoconstrictors or vasodilators. They often serve specific functions within vascular regulation. For example, NO is responsible for reducing shear stress from blood flow. This is done through endothelial glycocalyx, which starts a pathway that activates protein kinase B. The result is the increased activity of endothelial NO synthase (eNOS). This leads to vasodilation, reducing shear stress (Herring and Paterson, 2018).
Extrinsic Control: Autonomic Control
While blood vessels can act independently of each other with intrinsic regulation, several situations require coordinated adaptation. This is the responsibility of extrinsic regulators. As with intrinsic control, there are several mechanisms for this. The first is autonomic regulation. The autonomic nervous system is split into two components: sympathetic and parasympathetic. The former originates in the brainstem medulla, eventually terminating with postganglionic sympathetic neurons. These neurons send unmyelinated axons from the sympathetic chain and innervate blood vessels. Unlike intrinsic regulation, extrinsic regulation does not heavily target the arterioles. Instead, the sympathetic nervous system primarily innervates small arteries and veins. At sympathetic synapses, noradrenaline is released and binds to α1 receptors. This receptor is coupled to a Gq subunit and leads to depolarization of the smooth muscle, eventually causing vasoconstriction. While this is the case for most sympathetic fibres, some release acetylcholine, causing vasodilation (Herring and Paterson, 2018).
A few tissues are innervated by the vasodilatory parasympathetic system. This system originates from the vagus nerve and releases acetylcholine from the postganglionic fibres. This binds to M3 receptors which activate the Gq-mediated phospholipase C (PLC) pathway in endothelial cells. The result of this is increased NO production and vasodilation (Herring and Paterson, 2018).
Extrinsic Control: Hormonal Regulation
Vascular smooth muscle can also be controlled systemically by hormones. Several hormones influence contraction: adrenaline, angiotensin II, and vasopressin, among others. Each of these hormones is involved in supporting blood pressure during stress (Herring and Paterson, 2018). Adrenaline is produced by the adrenal medulla in response to stimulation from sympathetic fibres. This causes vasodilation in cardiac muscle, skeletal muscle, and the liver due to the presence of β2 receptors. These receptors are coupled to a Gs subunit, which as mentioned previously, reduces MLCK activity through the activation of protein kinase A. The expression of these receptors specifically in these tissues is significant, as they are heavily involved in the “fight or flight” response of the sympathetic nervous system. Angiotensin II acts through this system, as it can stimulate the sympathetic module. Vasopressin, on the other hand, acts as a vasoconstrictor through V1 receptors.
Extrinsic Control: Baroreflex
The baroreceptor reflex pathway is responsible for sensing changes in blood pressure during the cardiac cycle. This is coordinated by several baroreceptors, which fire in response to elevated blood pressure. There are primarily two types of baroreceptors: high-pressure arterial baroreceptors and low-pressure volume baroreceptors. The former are located within the carotid sinuses and the aortic arch; the latter are in the atria, ventricles, and pulmonary vasculature (Armstrong et al., 2023).
The baroreceptors provide input to the nucleus tractus solitarius (NTS) in the medulla. This area of the brain is responsible for controlling sympathetic and parasympathetic output. When blood pressure increases, baroreceptors start to fire. This is due to stretch-mediated activation in their respective locations. Increased stretch causes increased input to the NTS from the baroreceptors; this inhibits the sympathetic system and activates the parasympathetic system. As previously discussed, this results in vasodilation and a decrease in blood pressure. The opposite is true for a decrease in blood pressure; baroreceptors lower their firing rate and decrease input to the NTS, activating the sympathetic nervous system. Issues with baroreceptors, such as carotid sinus syndrome, can cause the reflex to be oversensitive. This can cause hypotension from slight pressures such as a tight collar (Armstrong et al., 2023).
Conclusion
Through exploring the different mechanisms for regulating the vascular smooth muscle, its importance to cardiovascular homeostasis becomes very clear. These mechanisms can be split into a hierarchy of control. At the bottom, intrinsic mechanisms are concerned with maintaining basal blood flow and distributing flow based on tissue requirements. The former is done through the Bayliss effect, where stretch-activated channels control the contraction of vascular myocytes. The latter can be controlled through metabolites such as adenosine or through factors such as NO. Moving up the hierarchy, extrinsic mechanisms are concerned with systemic changes. This can be modulated through the autonomic nervous system. Sympathetic fibres primarily induce vasoconstriction, with the parasympathetic system playing a role in a few tissues. This can be modulated by hormones and baroreceptors, often in response to changes in blood pressure. Issues in these regulatory mechanisms are often linked to various diseases. Therefore, it is of great importance that vascular regulation is studied further to elucidate any potential treatments.
Works Cited
Armstrong, Maggie, et al. “Physiology, Baroreceptors.” National LIbrary of Medicine, StatPearls Publishing, 6 Mar. 2023, www.ncbi.nlm.nih.gov/books/NBK538172/.
Herring, Neil, and David J Paterson. Levick’s Introduction to Cardiovascular Physiology. 6th ed., Boca Raton, Fl, Crc Press, 2018.
Klabunde, Richard E. Cardiovascular Physiology Concepts. 3rd ed., New York, Wolters Kluwer Medical, 2021.