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Regulation of Cerebral Blood Flow: Response to Cytochrome P450 Lipid Metabolites

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ABSTRACT

There have been numerous reviews related to the cerebral circulation. Most of these reviews are similar in many ways. In the present review, we thought it important to provide an overview of function with specific attention to details of cerebral arterial control related to brain homeostasis, maintenance of neuronal energy demands, and a unique perspective related to the role of astrocytes. A coming review in this series will discuss cerebral vascular development and unique properties of the neonatal circulation and developing brain, thus, many aspects of development are missing here. Similarly, a review of the response of the brain and cerebral circulation to heat stress has recently appeared in this series (8). By trying to make this review unique, some obvious topics were not discussed in lieu of others, which are from recent and provocative research such as endothelium‐derived hyperpolarizing factor, circadian regulation of proteins effecting cerebral blood flow, and unique properties of the neurovascular unit. © 2018 American Physiological Society. Compr Physiol 8:801‐821, 2018.

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Figure 1. Figure 1. Schematic representation of glucose metabolism. Glucose enters cells trough glucose transporters (GLUTs) and is phosphorylated by hexokinase (HK) to produce glucose‐6‐phosphate (glucose‐6P). Glucose‐6P can be processed into three main metabolic pathways. First, it can be metabolized through glycolysis (i), giving rise to two molecules of pyruvate and producing adenosine phosphate (ATP) and nicotinamide adenine dinucleotide (NADH). Pyruvate can then enter mitochondria, where it is metabolized through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (Ox Phos), producing ATP and CO2 while consuming oxygen. Pyruvate can otherwise be reduced to lactate‐by‐lactate dehydrogenase (LDH). This lactate can be released in the extracellular space through monocarboxylate transporters (MCTs). The complete oxidation of glucose produces larger amounts of energy in the form of ATP in the mitochondria (30‐34 ATP) compared to glycolysis (2 ATP). Alternatively, glucose‐6P can be processed through the pentose phosphate pathway (PPP) (ii), leading to the production of reducing equivalent in the form of nicotinamide adenine dinucleotide phosphate (NADPH). Note that the PPP and glycolysis are linked at the level of glyceraldehyde‐3‐phosphate (GA3P) and fructose‐6‐phosphate (fructose‐6P). Finally, in astrocytes, glucose‐6P can also be used to store glucosyl units as glycogen (iii). Abbreviations are as follows: GPI, glucose‐6‐phosphate isomerase; PFK, phosphofructokinase‐1; Fructose‐1,6‐P2, fructose‐1,6‐bisphosphate; DHAP, dihydroxyacetone phosphate; TPI, triose phosphate isomerase; G6PDH, glucose‐6‐phosphate dehydrogenase; 6‐PGL, 6‐phosphoglucono‐δ‐lactone; 6‐PG, 6‐phosphogluconate; 6 PGDH, 6‐phosphogluconate dehydrogenase; ribulose‐5P, ribulose‐5‐phosphate; ribose‐5P, ribose‐5‐phosphate; xylulose‐5P, xylulose‐5‐phosphate; TK, transketolase; sedoheptulose‐7P, sedoheptulose‐7‐phosphate; TA, transaldolase; and erythrose‐4P, erythrose‐4‐phosphate. (Reproduced, with permission, from Belanger M, Allaman I, and Magistretti PJ, 2011, .)
Figure 2. Figure 2. Dependence of brain activity on blood flow in response to initiation of different task performance as shown by functional MRI signals.
Figure 3. Figure 3. Schematic representation of a neurovascular unit with astrocytes being the central processor of neuronal signals as depicted in both panels A and panel B.
Figure 4. Figure 4. (A) Immunostaining depiction of components of the neurovascular unit (NVU). The astrocytes (stained with rhodamine labeled GFAP) shown in red. The neurons are stained with fluorescein tagged NSE shown in green and the blood vessels are stained with PECAM shown in blue. Note the location of the foot processes around the vasculature. (B) Histochemical localization of β‐galactosidase expression in rat brain following lateral ventricular infusion of Ad5/CMV‐β‐galactosidase (magnification × 1000). Note staining of astrocytes and astrocytic foot processes surrounding blood vessel emulating the exploded section of the immunostained brain slice.
Figure 5. Figure 5. Image taken using intravital microscopy via a two‐photon microscope system through a surgically implanted chronic cranial window in mice depicting projections of astrocyte foot processes contacting or touching cerebral microvessels shown using FITC‐dextran, green.
Figure 6. Figure 6. An increase in intraluminal pressure from 10 to 100 mmHg induces depolarization of arterial muscle cell via reduction in outward K+ current through Ca2+‐activated K+ channel (KCa) and K+ efflux leading to regenerative electrical spike activity stimulated by an increase in inward current carried by voltage‐gated L‐type Ca2+ channel causing arterial myocyte constriction.
Figure 7. Figure 7. Resting potential (Em = mV, ordinate) as a function of external K+ concentration [K]o (Log scale) for vascular smooth muscle cells of cat basilar artery. The data are represented as mean ± SD for 10 to 16 cells in seven different preparations.
Figure 8. Figure 8. Changes in morphology of astrocytes and cerebral capillary endothelial cells when cocultured. (A) Formation of capillary‐like structures (arrow) double‐labeled with acetylated LDL labelled with 1,1′‐dioctadecyl‐1,3,3,3′,3′‐tetramethyl‐indocarbocyanine perchlorate (DiI‐Ac‐LDL; red) and glial fibrillary acidic protein (GFAP; green) in the coculture of astrocytes and cerebral capillary endothelial cells. (B) Formation of capillary‐like structures (arrow) triple labeled by platelet endothelial cell adhesion molecule‐1 (PECAM‐1; green), GFAP (red), and 4,6‐diamidino‐2‐phenylindole (DAPI; blue) in the coculture of astrocytes and cerebral capillary endothelial cells. Note the interaction between astrocytes and endothelial tubes (arrowheads in A and B). (C) Double immunolabeling of blood vessels and astrocytes with PECAM‐1 (green) and GFAP (red) in a section from normal rat cortex showing astrocytes from foot processes that impinge on vessels (arrows). (D) Cells (*) forming tube identified by DAPI staining (E) in coculture exhibit punctate staining of connexin‐43 on their cell‐cell borders (arrow). Arrow points to area shown in the inset at higher magnification. (F) cells (*) outside tubes in the same coculture as in D show moderate to light cytoplasmic staining of connexin‐43. Bar in A = 25 μm for A and B, bar = 20 μm in C, bar in F = 10 μm for D to F, and bar in inset of D = 5 μm. (Reproduced, with permission, from Zhang C and Harder DR, 2002, .)
Figure 9. Figure 9. Rhythmic CYP epoxygenase expression and activity in endothelial cells. (A) RT‐PCR was used to measure the rhythmic mRNA expression of Cyp2c11 in rat brain microvascular endothelial cells. (B) Formation of 11,12‐EET from AA metabolism by CYP 2C11 epoxygenase in cultured endothelial cells was measured by LC/MS analysis. Cosinor analysis was used to test for 12 and 24‐h period rhythms. Phase Φ and P values are indicated for each graph.
Figure 10. Figure 10. Schematic diagram of possible signaling mechanisms in astrocytes and vascular smooth muscle that result in cerebrovascular vasodilation during hypoxemia. ADO, adenosine; ARA, arachidonic acid; DAG, diacylglycerol; GLT1, primary astrocytic glutamate transporter; Glu, glutamate; IP3, inositol triphosphate; mGluR, metabotropic glutamate receptor; PLA2, phospholipase A2; PLC, phospholipase C; CYP, cytochrome P‐450; EET, epoxyeicosatrienoic acids; TRPV4, transient receptor potential vanilloid 4; KCa, calcium‐activated K+; KIR, inwardly rectifying K+ channel; 20‐HETE, 20‐hydroxyeicosatetraenoic acid. Dashed line indicates negative effect. (Reproduced, with permission, from Liu X et al., 2015, .)


Figure 1. Schematic representation of glucose metabolism. Glucose enters cells trough glucose transporters (GLUTs) and is phosphorylated by hexokinase (HK) to produce glucose‐6‐phosphate (glucose‐6P). Glucose‐6P can be processed into three main metabolic pathways. First, it can be metabolized through glycolysis (i), giving rise to two molecules of pyruvate and producing adenosine phosphate (ATP) and nicotinamide adenine dinucleotide (NADH). Pyruvate can then enter mitochondria, where it is metabolized through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (Ox Phos), producing ATP and CO2 while consuming oxygen. Pyruvate can otherwise be reduced to lactate‐by‐lactate dehydrogenase (LDH). This lactate can be released in the extracellular space through monocarboxylate transporters (MCTs). The complete oxidation of glucose produces larger amounts of energy in the form of ATP in the mitochondria (30‐34 ATP) compared to glycolysis (2 ATP). Alternatively, glucose‐6P can be processed through the pentose phosphate pathway (PPP) (ii), leading to the production of reducing equivalent in the form of nicotinamide adenine dinucleotide phosphate (NADPH). Note that the PPP and glycolysis are linked at the level of glyceraldehyde‐3‐phosphate (GA3P) and fructose‐6‐phosphate (fructose‐6P). Finally, in astrocytes, glucose‐6P can also be used to store glucosyl units as glycogen (iii). Abbreviations are as follows: GPI, glucose‐6‐phosphate isomerase; PFK, phosphofructokinase‐1; Fructose‐1,6‐P2, fructose‐1,6‐bisphosphate; DHAP, dihydroxyacetone phosphate; TPI, triose phosphate isomerase; G6PDH, glucose‐6‐phosphate dehydrogenase; 6‐PGL, 6‐phosphoglucono‐δ‐lactone; 6‐PG, 6‐phosphogluconate; 6 PGDH, 6‐phosphogluconate dehydrogenase; ribulose‐5P, ribulose‐5‐phosphate; ribose‐5P, ribose‐5‐phosphate; xylulose‐5P, xylulose‐5‐phosphate; TK, transketolase; sedoheptulose‐7P, sedoheptulose‐7‐phosphate; TA, transaldolase; and erythrose‐4P, erythrose‐4‐phosphate. (Reproduced, with permission, from Belanger M, Allaman I, and Magistretti PJ, 2011, .)


Figure 2. Dependence of brain activity on blood flow in response to initiation of different task performance as shown by functional MRI signals.


Figure 3. Schematic representation of a neurovascular unit with astrocytes being the central processor of neuronal signals as depicted in both panels A and panel B.


Figure 4. (A) Immunostaining depiction of components of the neurovascular unit (NVU). The astrocytes (stained with rhodamine labeled GFAP) shown in red. The neurons are stained with fluorescein tagged NSE shown in green and the blood vessels are stained with PECAM shown in blue. Note the location of the foot processes around the vasculature. (B) Histochemical localization of β‐galactosidase expression in rat brain following lateral ventricular infusion of Ad5/CMV‐β‐galactosidase (magnification × 1000). Note staining of astrocytes and astrocytic foot processes surrounding blood vessel emulating the exploded section of the immunostained brain slice.


Figure 5. Image taken using intravital microscopy via a two‐photon microscope system through a surgically implanted chronic cranial window in mice depicting projections of astrocyte foot processes contacting or touching cerebral microvessels shown using FITC‐dextran, green.


Figure 6. An increase in intraluminal pressure from 10 to 100 mmHg induces depolarization of arterial muscle cell via reduction in outward K+ current through Ca2+‐activated K+ channel (KCa) and K+ efflux leading to regenerative electrical spike activity stimulated by an increase in inward current carried by voltage‐gated L‐type Ca2+ channel causing arterial myocyte constriction.


Figure 7. Resting potential (Em = mV, ordinate) as a function of external K+ concentration [K]o (Log scale) for vascular smooth muscle cells of cat basilar artery. The data are represented as mean ± SD for 10 to 16 cells in seven different preparations.


Figure 8. Changes in morphology of astrocytes and cerebral capillary endothelial cells when cocultured. (A) Formation of capillary‐like structures (arrow) double‐labeled with acetylated LDL labelled with 1,1′‐dioctadecyl‐1,3,3,3′,3′‐tetramethyl‐indocarbocyanine perchlorate (DiI‐Ac‐LDL; red) and glial fibrillary acidic protein (GFAP; green) in the coculture of astrocytes and cerebral capillary endothelial cells. (B) Formation of capillary‐like structures (arrow) triple labeled by platelet endothelial cell adhesion molecule‐1 (PECAM‐1; green), GFAP (red), and 4,6‐diamidino‐2‐phenylindole (DAPI; blue) in the coculture of astrocytes and cerebral capillary endothelial cells. Note the interaction between astrocytes and endothelial tubes (arrowheads in A and B). (C) Double immunolabeling of blood vessels and astrocytes with PECAM‐1 (green) and GFAP (red) in a section from normal rat cortex showing astrocytes from foot processes that impinge on vessels (arrows). (D) Cells (*) forming tube identified by DAPI staining (E) in coculture exhibit punctate staining of connexin‐43 on their cell‐cell borders (arrow). Arrow points to area shown in the inset at higher magnification. (F) cells (*) outside tubes in the same coculture as in D show moderate to light cytoplasmic staining of connexin‐43. Bar in A = 25 μm for A and B, bar = 20 μm in C, bar in F = 10 μm for D to F, and bar in inset of D = 5 μm. (Reproduced, with permission, from Zhang C and Harder DR, 2002, .)


Figure 9. Rhythmic CYP epoxygenase expression and activity in endothelial cells. (A) RT‐PCR was used to measure the rhythmic mRNA expression of Cyp2c11 in rat brain microvascular endothelial cells. (B) Formation of 11,12‐EET from AA metabolism by CYP 2C11 epoxygenase in cultured endothelial cells was measured by LC/MS analysis. Cosinor analysis was used to test for 12 and 24‐h period rhythms. Phase Φ and P values are indicated for each graph.


Figure 10. Schematic diagram of possible signaling mechanisms in astrocytes and vascular smooth muscle that result in cerebrovascular vasodilation during hypoxemia. ADO, adenosine; ARA, arachidonic acid; DAG, diacylglycerol; GLT1, primary astrocytic glutamate transporter; Glu, glutamate; IP3, inositol triphosphate; mGluR, metabotropic glutamate receptor; PLA2, phospholipase A2; PLC, phospholipase C; CYP, cytochrome P‐450; EET, epoxyeicosatrienoic acids; TRPV4, transient receptor potential vanilloid 4; KCa, calcium‐activated K+; KIR, inwardly rectifying K+ channel; 20‐HETE, 20‐hydroxyeicosatetraenoic acid. Dashed line indicates negative effect. (Reproduced, with permission, from Liu X et al., 2015, .)
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Teaching Material

D. R. Harder, K. R. Rarick, D. Gebremedhin, S. S. Cohen. Regulation of Cerebral Blood Flow: Response to Cytochrome P450 Lipid Metabolites. Compr Physiol. 8: 2018, 801-821.

Didactic Synopsis

Major Teaching Points:

  1. The high level of neuronal activity requires tight regulation of the cerebral vasculature to provide constant blood flow to maintain adequate energy substrate and neuronal health.
  2. The myogenic autoregulation of cerebral blood flow is a critical homeostatic mechanism that protects against blood pressure fluctuations and maintains constant blood flow to supply oxygen and nutrients.
  3. The neurovascular unit comprising of astrocytes, neurons, and the cerebral arterioles functions to compensate neuronal metabolic demand by coupling neuronal activity to cerebral blood flow.
  4. Impaired autoregulation of cerebral blood flow results in passive reductions or increases in cerebral blood flow leading to ischemic vascular damage or perfusion injuries including edema and blood-brain barrier breakdown.
  5. Dysregulation of neurovascular coupling is known to occur in conditions such as stroke, diabetes, traumatic brain injury, and also in neurodegenerative disorders including dementia and Alzheimer's disease.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Glucose enters neuronal cells via specific transporters (GLUTs), where it is phosphorylated by hexokinase to produce glucose-6-phosphate which is then processed through an array of metabolic pathways; these pathways involve mitochondrial metabolism, the pentose phosphate pathway, and gluconeogenesis. Through these pathways glucose is nearly completely oxidized to carbon dioxide and water.

Figure 2. Teaching points: The dependence of brain activity on blood flow in response to cognitive tasks is depicted in these functional MRI signals in response to initiation of brain activity.

Figure 3. Teaching points: The functional cellular organization of the brain is such that neurons, through chemical signals to astrocytes, signal vascular smooth muscle to dilate, increasing blood flow, and, thereby, meeting metabolic demand. Such activity occurs in discrete cellular clustering of neurons, astrocytes, and microvessels forming the neurovascular unit (NVU).

Figure 4. Teaching points: Astrocytes are visualized by immunostaining with antiglial fibrillary acidic protein (red). These astrocytes are surrounded by neurons labeled using antineuron specific enolase (green). Neurons and astrocytes are surrounded by the cerebral microcirculation (anti-PECAM blue) completing the NVU. The importance of astrocytes to regulate the cerebral circulation and mediate neurovascular coupling is suggested by the astrocyte's central location within the NVU and the close interaction of foot processes impinging on the microcirculation.

Figure 5. Teaching points: Signaling molecules released by astrocytes which act to dilate cerebral arterioles will reduce vascular tone increasing blood flow in response to neuronal metabolic demand. The views depicted here come from the cortex; however, as astrocytes make up over 60% of the cell mass in the brain, such NVU-dependent regulation occurs throughout all brain regions.

Figure 6. Teaching points: This process can be observed in isolated cannulated, pressurized arteries exhibiting regenerative electrical spike activity, the frequency and rate of rise of which increases as transmural pressure increases. Not all investigators observe regenerative electrical activity, but do measure vascular muscle depolarization.

Figure 7. Teaching points: Arterial smooth muscle cells depolarize with an average slope of between 50 and 60 mV/decade changes in [K]o. A rise in [K]o from 4 to 12 mmol/L results in hyperpolarization in that the Na/K ATPase saturates at a [K]o of 12 mV exerting a hyperpolarizing influence of up to 10 mV; other reasons for the [K]o-mediated hyperpolarization are discussed in the text. This figure depicts a classic Em versus log [K]o curve as described in constant field theory.

Figure 8. Teaching points: These data confirm other's work and clearly demonstrate that metabolites of AA formed via CYP epoxygenase by astrocytes uncovers a novel mechanism in brain angiogenesis and support a key role of astrocytes in regulating blood flow to meet neuronal metabolic demand.

Figure 9. Teaching points: Conserved transcriptional elements in CYP gene promoter regions can underlie circadian changes in expression and activity of CYP enzymes controlling blood flow. These changes are in response to cellular clock genes which can be found in different cell types.

Figure 10. Teaching points: A hypothesis can be extended to formation of 20-HETE which is oxygen dependent (43). Pharmacological reduction in 20-HETE levels increase CBF, whereas, 20-HETE alone leads to reduced blood flow under hypoxic states.


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How to Cite

David R. Harder, Kevin R. Rarick, Debebe Gebremedhin, Susan S. Cohen. Regulation of Cerebral Blood Flow: Response to Cytochrome P450 Lipid Metabolites. Compr Physiol 2018, 8: 801-821. doi: 10.1002/cphy.c170025