Cerebral Vascular Biology in Health and Disease

Key Points

Cerebral artery tone is substantially modulated under physiologic conditions by endothelium-derived nitric oxide, by reactive oxygen species, and through hyperpolarization mediated by several types of K ⁺ channels.
Cerebral vascular function is very sensitive to endothelial dysfunction that occurs during chronic disease, resulting in impairment of vasodilator mechanisms.
Oxidative stress and inflammation occur in the cerebral circulation in response to cardiovascular risk factors present during atherosclerosis and chronic hypertension, such as elevated plasma levels of cholesterol and angiotensin II, respectively.

Introduction

The brain has a limited supply of nutrients; thus normal brain function relies on adequate perfusion by the cerebral circulation for the delivery of oxygen and nutrients, as well as the removal of waste products. It is for this reason that cerebral vascular tone is tightly regulated, and why any alterations in mechanisms that modulate cerebral vessel function can predispose to cerebrovascular disease and stroke. Atherosclerosis is the underlying pathologic process for both coronary and cerebral artery disease, which are the two most common forms of cardiovascular disease.

The purpose of this chapter is thus to provide insight into major mechanisms that regulate cerebral artery function, and alterations in these mechanisms in two major clinical conditions that have a significant negative impact on health worldwide—hypertension and atherosclerosis. The scope is mostly limited to discussion of cerebral blood vessels and mechanisms that regulate their tone, either under basal conditions or in response to physiologically relevant agonists.

Organization of the Cerebral Circulation

The brain is predominantly perfused by three pairs of intracranial arteries: the anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA, respectively). These arise from the circle of Willis, a ring of arteries formed by the anterior and posterior communicating arteries that connect the terminal ends of the basilar and internal carotid arteries. The ACA, MCA, and PCA travel along the pial surface of the brain, branching into smaller arterioles. Importantly, anastomoses exist between the smaller arterioles of these three major arterial trees, and collateral flow is thought to be important when blood flow in one region is compromised. The pial arterioles then dive into the brain to give rise to parenchymal arterioles. Parenchymal arterioles are long, relatively unbranched arterioles that perfuse a distinct area of brain tissue. The capillary network arises from the parenchymal arterioles, which is where the majority of nutrient and gas exchange occurs. Although much less is known about their function during health or disease, cerebral venules and veins are also important components of the cerebral circulation. For example, major disruption to blood-brain barrier function during acute hypertension occurs in the pial venules.

Physiologic Regulation of Cerebral Vascular Tone

Numerous mechanisms regulate cerebral artery function. Most of the recent experimental evidence regarding such mechanisms has come from pharmacologic studies and the use of genetically modified mice. Major mechanisms include the release of nitric oxide (NO) from the endothelium to underlying smooth muscle cells (discussed in the Nitric Oxide and Cyclic Guanosine Monophosphate section); potassium ion (K ⁺ ) channels (see K ⁺ Channels), which includes a discussion of the newly described two-pore domain (K _2P ) channels, Rho/Rho-kinase activity (see RhoA/Rho-Kinase); reactive oxygen species (ROS), which are discussed in the Reactive Oxygen Species section; and the recently described transient receptor potential (TRP) channels (discussed in the Transient Receptor Potential Channels section).

Nitric Oxide and Cyclic Guanosine Monophosphate

A major mechanism for maintenance of vascular tone by the endothelium involves the production of endothelium-derived NO. In endothelium, NO is synthesized from endothelial nitric oxide synthase (eNOS); it then diffuses to the underlying smooth muscle, where it activates soluble guanylate cyclase, which in turn leads to increased intracellular cyclic guanosine monophosphate levels and subsequent relaxation of the smooth muscle. Experimental evidence for modulation of cerebral vascular tone by endothelium-derived NO has been obtained by applying inhibitors of NOS to cerebral blood vessels from several different species, both in vivo and in vitro, and has involved such inhibitors causing vasoconstriction (reviewed extensively in Faraci and Heistad ).

NO release from the endothelium can also be stimulated in response to receptor- (e.g., acetylcholine, bradykinin) or non-receptor-mediated agonists, or in response to shear stress. Endothelium-dependent, NO-mediated cerebral vascular relaxation in response to such agonists is often used to determine the functional integrity of the endothelium. Endothelial dysfunction, manifested as diminished NO bioavailability experimentally by impaired endothelium-dependent vasodilation, or reduced vasoconstriction in response to a NOS inhibitor, is a common feature of many cerebrovascular-related diseases (discussed in the Alterations in Cerebral Vascular Function During Hypertension and Atherosclerosis section). Such exogenously applied agonists are often useful in this way experimentally, and they may also be important endogenously. For example, neurovascular coupling in some brain regions is mediated by neuronally released acetylcholine acting on the endothelium to stimulate eNOS.

K ⁺ Channels

The activity of K ⁺ channels is a major regulator of smooth muscle cell membrane potential and, as such, is an important regulator of vascular tone. This is because vessel diameter is in large part dependent on cytosolic Ca ²⁺ concentration, which in turn is dependent on membrane potential. There are five major types of K ⁺ channels known to be expressed in cerebral blood vessels: calcium (Ca ²⁺ )-activated (K _Ca ) K ⁺ channels, ATP sensitive K ⁺ (K _ATP ) channels, voltage-sensitive K ⁺ (K _V ) channels, inwardly rectifying K ⁺ (K _IR ) channels, and tandem-pore (TREK-1) channels, and all are regulators of vascular tone. This is supported by the wealth of information using both pharmacologic inhibitors and gene-targeted mice to study the regulation of membrane potential and vascular function. Potassium channels are also important mediators of vasodilator responses to several vasodilators that regulate vascular tone, and this will be also be discussed.

K _Ca -Activated K ⁺ Channels

There are three subtypes of K _Ca channels present in the vasculature: large-conductance K _Ca (BK _Ca ) channels, intermediate-conductance (IK _Ca ) channels, and small-conductance (SK _Ca ) channels. Most research regarding the functional importance of this channel, especially in cerebral arteries, has centered around the BK _Ca channel.

As the name suggests, these channels are activated in response to increases in intracellular Ca ²⁺ . Membrane depolarization, myogenic responses (i.e., pressure-induced vasoconstriction, important in development and maintenance of basal vascular tone), and elevations in arterial pressure are associated with elevations in intracellular Ca ²⁺ concentration in cells of the vasculature. Thus an important function of these channels appears to be to act as a negative feedback mechanism during increases in Ca ²⁺ to limit vasoconstriction. A major mechanism of elevations in intracellular Ca ²⁺ appears to be via Ca ²⁺ sparks, which are localized elevations in cytosolic Ca ²⁺ , due to the opening of ryanodine-sensitive Ca ²⁺ release channels in the sarcoplasmic reticulum to K _Ca channels located on the plasma membrane.

These channels are important in modulating the basal tone of cerebral arteries, as selective inhibition of BK _Ca channels with tetraethylammonium ion (TEA) produces vasoconstriction. In mice deficient in the β1 subunit of BK _Ca channels, increased intracellular Ca ²⁺ concentration in response to ryanodine (which at low concentrations depletes Ca ²⁺ stores from the sarcoplasmic reticulum so that intracellular Ca ²⁺ concentration increases) and cerebral vascular constriction to iberiotoxin (selective inhibitor of BK _Ca channels) was reduced, suggesting that Ca ²⁺ spark activity modulates myogenic tone through BK _Ca channel activation. These channels may be more important in the modulation of basal tone in larger cerebral arteries.

Recent evidence of the importance of Ca ²⁺ spark activity and BK _Ca channels as mediators of vasodilators has emerged, as TEA and iberiotoxin inhibit vasodilator responses in response to vasodilators that activate adenylate cyclase and guanylate cyclase. Acidosis markedly increased Ca ²⁺ spark activity and caused dilatation of brain parenchymal arterioles. Dilatation was inhibited by inhibitors of ryanodine receptors (ryanodine) and BK _Ca channels (paxilline), as well as in mice lacking the BK _Ca channel. Hydrogen sulfide (an important signaling molecule in the regulation of vascular tone and blood pressure) also increased Ca ²⁺ spark and BK _Ca current frequency, as well as causing dilatation in cerebral arterioles—the vasodilatation was inhibited by ryanodine and iberiotoxin, suggesting Ca ²⁺ spark activity is important in the response. Intermittent hypoxia increased myogenic tone through loss of hydrogen sulfide activation of K _Ca channels. Hypoxia had no effect on Ca ²⁺ spark frequency but reduced K _Ca channel activity. Protein expression of K _Ca 2.2, 2.3, and 3.1, ¹⁶ as well as α- and β1-subunits of BK _Ca channels in cerebral arteries, have been reported.

K _ATP Channels

K _ATP channels are defined by their sensitivity to intracellular ATP, with their activity being inhibited by intracellular ATP. Generally, the intracellular concentration of ATP is normally sufficient that these channels have a low open probability in most vascular smooth muscle cells under normal conditions, and this appears to also be the case in the cerebral circulation, where glibenclamide, a selective inhibitor of K _ATP channels, has no effect on cerebral vascular tone. However, K _ATP channels appear to be present and functional in cerebral vessels based on direct evidence for their expression (discussed as follows) and a wealth of evidence reporting glibenclamide-sensitive relaxation of cerebral arteries in response to K _ATP channel activators.

Several more recent studies have investigated the expression of K _ATP in cerebral vessels. K _ATP channels are thought to be a hetero-multimeric complex of two subunits: one is a pore-forming inward-rectifying K ⁺ channel type 6 (i.e., 6.1 or 6.2), and the other is a sulfonylurea receptor (SUR), either SUR1 and SUR2, with the SUR2 gene generating the two splice variants SUR2A and SUR2B. Messenger RNA (mRNA) expression for both the pore-forming subunits (K _IR 6.1 and 6.2) and SUR1, 2A, and 2B has been demonstrated in cerebral arteries, ^, although another study investigating SUR expression found no expression of SUR1 and reported only SUR2B expression. Protein expression of K _IR 6.1 and 6.2, as well as SUR1 and 2B, was also reported. Cerebral arterioles were found to express K _IR 6.1 and SUR2B, with human cerebral arteries found to express SUR2B.

Acidosis and reductions in intracellular pO ₂ are known to produce cerebral vasodilatation. K _ATP channels have been shown to be involved in cerebral vasodilatation in response to acidosis, ^, as well as in vasodilatation to NMDA, which may be important in the coupling of cerebral metabolism and blood flow. More direct evidence for a role of K _ATP channels in mediating vasodilatation in response to oxygen/glucose deprivation was reported in that vasodilatation was impaired in SUR-deficient compared with wild-type mice. Myogenic tone, and vasodilatation in response to hypoxia, are not dependent on SUR2 expression, although relaxation to hypoxia is inhibited by glibenclamide, ^, suggesting a role for K _ATP channels in hypoxia-induced vasodilatation where the K _ATP subunit composition does not involve SUR2. Hydrogen sulfide also dilates cerebral arteries, an effect that is inhibited by glibenclamide and in SUR2-deficient mice.

K _V Channels

K _V channels are activated in response to increases in pressure in cerebral arteries and modulate cerebral vascular tone, in that pharmacologic inhibition of K _V channels with 4-aminopyridine causes cerebral artery depolarization and constriction. ^, K _V channels are also known to mediate cerebral artery dilations, including in response to NO. ^, K _V channel subunits are expressed in cerebral vessels (e.g., K _V 1.2 and 1.5, and K _V 2.1 and 2.2 ^, )—including in humans. K _V 2-mediated current is proposed to underlie K _V -dependent modulation of cerebral artery tone in that inhibition of the K _V 2 channel with stromatoxin-caused cerebral artery constriction.

K _IR Channels

This channel is so named since it conducts K ⁺ current more readily into than out of the cell over a wide range of membrane potentials. However, at membrane potentials within the physiologic range, these channels actually conduct a small outward current. Consequently, when this channel is inhibited with the pharmacologic blocker, barium ion (Ba ²⁺ ), depolarization and constriction of cerebral arteries are observed. Furthermore, in mice lacking the K _IR 2.1 subunit—the subunit thought to be important in mediating vascular K _IR current—cerebral artery K _IR channel currents are absent.

In the cerebral circulation, K ⁺ is released during neuronal activity and may be siphoned to cerebral vessels directly by astrocytes after neuronal activation. Basal concentration of K ⁺ in cerebrospinal fluid is ∼3 mM and may increase to between 4 and 7 mM during neuronal activity. In this concentration range (i.e., from 3 to 10 mM), K ⁺ causes dilatation of cerebral arteries ^, ^, ^, and arterioles. ^, ^, ^, Moreover, K ⁺ -induced hyperpolarization and vasodilatation in this concentration range are inhibited by Ba ²⁺ , ^, ^, ^, suggesting K _IR -mediated K ⁺ -induced vasodilation may be an important mechanism in the coupling of cerebral metabolism and blood flow (neurovascular coupling). Furthermore, cerebral vascular relaxation responses to K ⁺ are absent in mice lacking the K _IR 2.1 subunit. There have been reports of K _IR 2.1 channel expression in cerebral arteries. ^, Regarding the role for K _IR 2.1 channels in neurovascular coupling, recent work identified K _IR 2.1 channel on capillaries as critical for sensing neuronal activity (via K+ release) and initiating a retrograde signal to dilate upstream arterioles, thereby increasing local blood flow.

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Key Points

Introduction

Organization of the Cerebral Circulation

Physiologic Regulation of Cerebral Vascular Tone

Nitric Oxide and Cyclic Guanosine Monophosphate

K + Channels

K Ca -Activated K + Channels

K ATP Channels

K V Channels

K IR Channels