Haemodynamic response

In haemodynamics, the body must respond to physical activities, external temperature, and other factors by homeostatically adjusting its blood flow to deliver nutrients such as oxygen and glucose to stressed tissues and allow them to function. Haemodynamic response (HR) allows the rapid delivery of blood to active neuronal tissues. The brain consumes large amounts of energy but does not have a reservoir of stored energy substrates. Since higher processes in the brain occur almost constantly, cerebral blood flow is essential for the maintenance of neurons, astrocytes, and other cells of the brain. The coupling between neuronal activity and blood flow is neurovascular coupling.

Vascular anatomy overview In order to understand how blood is delivered to cranial tissues, it is important to understand the vascular anatomy of the space itself. Large cerebral arteries in the brain split into smaller arterioles, also known as pial arteries. These consist of endothelial cells and smooth muscle cells, and as these pial arteries further branch and run deeper into the brain, they associate with glial cells, namely astrocytes. The intracerebral arterioles and capillaries are unlike systemic arterioles and capillaries in that they do not readily allow substances to diffuse through them; they are connected by tight junctions in order to form the blood brain barrier (BBB). Endothelial cells, smooth muscle, neurons, astrocytes, and pericytes work together in the brain order to maintain the BBB while still delivering nutrients to tissues and adjusting blood flow in the intracranial space to maintain homeostasis. As they work as a functional neurovascular unit, alterations in their interactions at the cellular level can impair HR in the brain and lead to deviations in normal nervous function.

Mechanisms Various cell types play a role in HR, including astrocytes, smooth muscle cells, endothelial cells of blood vessels, and pericytes. These cells control whether the vessels are constricted or dilated, which dictates the amount of oxygen and glucose that is able to reach the neuronal tissue.

Astrocytes Astrocytes are unique in that they are intermediaries that lie between blood vessels and neurons. They are able to communicate with other astrocytes via gap junctions and have endfoot processes that interact with neuronal synapses. These processes have the ability to take up various neurotransmitters, such as norepinephrine (NE) and glutamate, and perform various other functions to maintain chemical and electrical homeostasis in the neuronal environment. Constriction has been shown in vitro to occur when NE is placed in the synapse and is taken up by astrocyte receptors. NE uptake leads to an increase in intracellular astrocyte Ca2+. When these calcium ion waves spread down the length of the astrocyte, phospholipase A (PLA2) is activated which in turn mobilizes arachidonic acid. These two compounds are transported to the smooth muscle and there react with cytochrome P450 to make 20-hydroxyeicosatetraenoic acid (20-HETE), which acts through yet to-be-determined mechanisms to induce vasoconstriction. It has also been shown that agonists of metabotropic glutamate receptors (mGluR) also increase intracellular Ca2+ to produce constriction.

Smooth muscle Dilation occurs when nitric oxide (NO) is released from endothelial cells and diffuses into nearby vascular smooth muscle. Several proposed pathways of NO-induced vasodilation have been proposed through haemodynamic investigation. It has been shown that NO inhibits 20-HETE synthesis, which may interfere with astrocytes' constriction pathways and lead to vasodilation. It has also been proposed that NO may amplify astrocyte Ca2+ influx and activate Ca2+-dependent potassium channels, releasing K+ into the interstitial space and inducing hyperpolarization of smooth muscle cells. In addition to this, it has already been shown that NO stimulates increased cyclic GMP (cGMP) levels in the smooth muscle cells, inducing a signaling cascade that results in the activation of cGMP-dependent protein kinase (PKG) and an ultimate decrease in smooth muscle Ca2+ concentration. This leads to a decrease in muscle contraction and a subsequent dilation of the blood vessel. Whether the vessels are constricted or dilated dictates the amount of oxygen and glucose that is able to reach the neuronal tissue.

Pericytes A principal function of pericytes is to interact with astrocytes, smooth muscle cells, and other intracranial cells to form the blood brain barrier and to modulate the size of blood vessels to ensure proper delivery and distribution of oxygen and nutrients to neuronal tissues. Pericytes have both cholinergic (α2) and adrenergic (β2) receptors. Stimulation of the latter leads to vessel relaxation, while stimulation of the cholinergic receptors leads to contraction. Paracrine activity and oxygen availability have been shown to also modulate pericyte activity. The peptides angiotensin II and endothelin-1 (ET-1) bind to pericytes and are vasoactive. Endothelial cells induce expression of endothelin-1, which leads to NO production and vasodilation. Experiments have demonstrated that oxygen levels also alter pericyte contraction and subsequent blood vessel contraction. In vitro, high oxygen concentrations cause pericyte constriction, while high CO2 concentrations cause relaxation. This suggests that pericytes may have the ability to dilate blood vessels when oxygen is in demand and constrict them when it is in surplus, modifying the rate of blood flow to tissues depending on their metabolic activity.

Complications The haemodynamic response is rapid delivery of blood to active neuronal tissue. Complications in this response arise in acute coronary syndromes and pulmonary arterial hypertension. These complications lead to a change in the regulation of blood flow to the brain, and in turn the amount of glucose and oxygen that is supplied to neurons, which may have serious effects not only on the functioning of the nervous system, but functioning of all bodily systems.

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