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Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

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ABSTRACT

Mitochondria not only produce energy in the form of ATP to support the activities of cells comprising the neurovascular unit, but mitochondrial events, such as depolarization and/or ROS release, also initiate signaling events which protect the endothelium and neurons against lethal stresses via pre‐/postconditioning as well as promote changes in cerebral vascular tone. Mitochondrial depolarization in vascular smooth muscle (VSM), via pharmacological activation of the ATP‐dependent potassium channels on the inner mitochondrial membrane (mitoKATP channels), leads to vasorelaxation through generation of calcium sparks by the sarcoplasmic reticulum and subsequent downstream signaling mechanisms. Increased release of ROS by mitochondria has similar effects. Relaxation of VSM can also be indirectly achieved via actions of nitric oxide (NO) and other vasoactive agents produced by endothelium, perivascular and parenchymal nerves, and astroglia following mitochondrial activation. Additionally, NO production following mitochondrial activation is involved in neuronal preconditioning. Cerebral arteries from female rats have greater mitochondrial mass and respiration and enhanced cerebral arterial dilation to mitochondrial activators. Preexisting chronic conditions such as insulin resistance and/or diabetes impair mitoKATP channel relaxation of cerebral arteries and preconditioning. Surprisingly, mitoKATP channel function after transient ischemia appears to be retained in the endothelium of large cerebral arteries despite generalized cerebral vascular dysfunction. Thus, mitochondrial mechanisms may represent the elusive signaling link between metabolic rate and blood flow as well as mediators of vascular change according to physiological status. Mitochondrial mechanisms are an important, but underutilized target for improving vascular function and decreasing brain injury in stroke patients. © 2016 American Physiological Society. Compr Physiol 6:1529‐1548, 2016.

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Figure 1. Figure 1. Electron microscopy section of a small branch of the MCA representative of 10‐ to 12‐week‐old, male Sprague Dawley (SD) rats showing differences in size, morphology, and relationship to other cellular structures of mitochondria in VSM and endothelium. Mitochondria in VSM form large fields with interspersed SR, whereas mitochondria in endothelium seem to be present singly. Rats were euthanized with anesthesia and perfused with a PBS solution containing 2% glutaraldehyde and 3% formaldehyde. Arteries were removed and kept in the perfusion solution for 1 h and post fixed in 1% osmium tetroxide and embedded in Spurr's resin. Ultrathin sections (80–90 nm) were mounted on formvar‐coated copper grids (200 mesh), air dried, and stained with uranyl acetate and lead citrate (at 7 and 7 min, respectively). The sections were put on grids and viewed at a magnification of 11,000× using a FEI Tecnai Bio Twin 120 keV TEM with a digital imaging setup (Wake Forest University Health Sciences, Winston‐Salem, NC). M, mitochondrion; SR, sarcoplasmic reticulum, IEL, internal elastic lamina, VSM, vascular smooth muscle. Magnification is 11,000×.
Figure 2. Figure 2. Electron microscopy section of an MCA representative of 10‐ to 12‐week‐old, female SD rats showing numerous sites of close association of mitochondria in different VSM cells. Several VSM cells with extensive mitochondrial fields are present, and multiple sites of close approximation of adjacent mitochondria are seen. Similar mitochondrial fields and connections in VSM are seen in male arteries. White arrows show examples of close mitochondrial connections. Black arrow shows a stressed mitochondrion. Magnification is 11,000×.
Figure 3. Figure 3. Higher magnification of mitochondrial connections in a VSM cell representative of 10‐ to 12‐week‐old, female SD rats. Numerous apparent contacts between mitochondria (examples shown by white arrows) as well as close approximation of mitochondria and SR. Magnification is 23,000×.
Figure 4. Figure 4. Electron microscopy section of a microvessel in brain parenchyma representative of 10‐ to 12‐week‐old, female SD rats showing a surrounding pericyte with a large mitochondrion as well as mitochondria in astrocytic endfeet. The pericytes and especially astroglial endfeet surround the parenchymal blood vessels and both cell types contain pronounced mitochondria. Magnification is 11,000×. M = mitochondrion, * = astroglial endfoot.
Figure 5. Figure 5. Electron microscopy section of brain parenchyma showing close approximation of microvessel representative of 10‐ to 12‐week‐old, male Zucker lean rats showing glial endfoot with prominent mitochondria. Lean Zucker rats are phenotypically normal and the mitochondria of the cerebral vasculature show no obvious differences with non‐IR rat strains. Magnification 11,000×.
Figure 6. Figure 6. Electron microscopy section of a pial artery representative of 10‐ to 12‐week‐old, male Zucker lean rats showing multiple mitochondria on glia limitans comprising the surface of cerebral cortex as well as in cell layers in adventitial connective tissues and nerves. Fields of mitochondria in astrocytes are shown in the white oval areas and the dashed rectangle corresponds to the area of the section enlarged in Figure . Magnification 1900×.
Figure 7. Figure 7. Higher magnification of indicated section of Figure showing numerous mitochondria in perivascular tissue. White oval shows mitochondrial field in VSM and black oval shows mitochondrial in adventitia. M, mitochondrion, VSM, vascular smooth muscle. Magnification 11,000×.
Figure 8. Figure 8. Electron microscopy section of a MCA representative of 10‐ to 12‐week‐old SD rats showing perivascular innervation. Mitochondria are prominent features in nerve terminals. Myelinated and nonmyelinated nerves are seen associated with the adventitia. M, mitochondrion. Magnification is 30,000×.
Figure 9. Figure 9. Electron microscopy section showing the VSM of a cerebral artery representative of 10‐ to 12‐week‐old, male rats showing damage to mitochondria in VSM at 48 h of reperfusion following 90 min of transient MCA occlusion. Mitochondria appear to be swollen and/or have lost the typical morphology including uniform cristae. Mitochondria in VSM cells following ischemia can have diverse features ranging from a normal appearance or show limited or extensive damage. Nonetheless, dilator responses to sodium nitroprusside, a VSM specific stimulus, are intact following ischemia. Magnification 11,000×.
Figure 10. Figure 10. Schematic illustration showing the primary signaling pathway involving NO production and S6K phosphorylation linking mitochondrial activation with preconditioning of cultured neurons against OGD. (A) All neurons were exposed to OGD. Diazoxide (DZ) protected neurons against OGD. Protection was eliminated by NOS inhibition and restored with NO donors. DZ, diazoxide; SNP, sodium nitroprusside; DEANO, (CH3CH2)2N–N(N=O)O Na+ x H2O. Values are mean ± SEM. *P < 0.05, compared to DZ treated, #P < 0.05, compared with untreated or DZ+L‐NAME treated neurons. Data adapted from (). (B) Preconditioning by neurons was eliminated by coadministration of siRNA against S6K. Values are mean ± SEM, *P < 0.05, compared with DZ preconditioning against OGD. Data adapted from (). (C‐E) Preconditioning by diazoxide enhanced the levels of phosphorylated/total of Akt, mTOR, and S6K and coadministration of L‐NAME reversed this effect during OGD. Values are mean ± SD. DZ, diazoxide, #P < 0.05, compared with no treatment prior to OGD. Data adapted from ().
Figure 11. Figure 11. Demonstration that BMS‐191096 is able to depolarize mitochondria in VSM without eliciting an increase in mitochondrial ROS production. (A) Original tracings showing ESR values for vehicle versus BMS‐191095 and diazoxide for denuded cerebral arteries. (B) ESR analysis showed diazoxide but not BMS‐191095 increased mitochondrial ROS generation in denuded cerebral arteries. (C and D) Original confocal images and summary data showing that diazoxide but not BMS‐191095 increased mitoSOX intensity in VSM. (E and F) Original confocal images and summary data illustrating that BMS‐191095 depolarized (loss of intensity) VSM. Data (means ± SEM) and for graphs and images are from (). *P < 0.05, compared with vehicle.
Figure 12. Figure 12. Schematic illustration showing signaling pathways linking mitochondrial depolarization in different cell types of the neurovascular unit to changes in cerebral vascular tone. The intrinsic VSM response involves mitochondria‐SR interactions resulting in enhanced calcium sparks activity. The extrinsic VSM response involves the effects of vasoactive stimuli such as NO on VSM tone via a cGMP‐linked mechanism. *, phosphorylated state.
Figure 13. Figure 13. Sex dependent differences in mitochondrial dynamics in large cerebral arteries from young rats. (A) Oxygen consumption was greater in 8‐ to 10‐week‐old SD female than male cerebral arteries during treatment with inhibitors of mitochondrial complexes and FCCP. (B) The protein mass of inner mitochondrial membrane proteins such as those composing Complex I were larger in female compared with male cerebral arteries. (C) The protein mass of outer mitochondrial membrane proteins such as those composing VDAC were larger in female compared with male cerebral arteries. (D) Dilation to diazoxide was greater in female compared with male isolated and pressurized MCAs. Data (means ± SEM) are from (). *P < 0.05, compared with male.
Figure 14. Figure 14. Demonstration that transient ischemia reduces dilation of MCAs to acetylcholine, bradykinin, and sodium nitroprusside but not to diazoxide in pressurized, isolated MCAs from 8‐ to 10‐week‐old, male rats. Surprisingly, dilator responses to acetylcholine, bradykinin, and especially diazoxide were reduced in arteries not directly exposed to cessation of blood flow. *P < 0.05, side ipsilateral (IPSI) to stroke compared with sham control, P < 0.05, IPSI compared to sham control, P < 0.05, compared to contralateral side (CONTRA). Data (means ± SEM) adapted from ().
Figure 15. Figure 15. Retained dilation of pressurized, isolated MCAs from 8‐ to 10‐week‐old, male rats following ischemia is due to mitochondrial activation in endothelium and not VSM. (A) Approximately one‐half of all dilation to diazoxide in Sham, control MCAs is due to endothelial factors while the remainder is due to VSM. In contrast, the retained dilation following ischemia in MCAs is due solely to endothelium. Denudation reduced dilation more in Sham than Ipsi arteries. (B) Phosphorylation of eNOS is greater in previously ischemic MCAs, which is consistent with a greater endothelial contribution to the retained dilation. *P < 0.05, compared with Sham. (C) Calcium sparks activity during basal conditions is reduced in previously ischemic MCAs and does not increase substantially in the presence of diazoxide. Unpublished data (means ± SEM) for panel C were generated using previously published methods () from MCA of male SD rats 48 h after 90 min of ischemia. IPSI represents artery that was occluded and Sham represents a corresponding MCA that was not ischemic from a Sham operated rat. *P < 0.05, compared with Sham. n = 14 images for Sham and Ipsi arteries. (D) Representative electron microscopic image shows areas of VSM where mitochondrial damage is apparent which accounts for decreased calcium sparks activity. Data (means ± SEM) for A and B are from ().
Figure 16. Figure 16. Schematic illustration of mitochondrial influences on cell types within the neurovascular unit. All cell types within the neurovascular unit are capable of affecting cerebral vascular tone through their mitochondrial mechanisms. Although the majority of mitochondria in the neurovascular unit can be simultaneously affected by insults such as ischemia or cortical spreading depression, it is more likely that only limited populations of mitochondrial are activated during changes in physiological status. For example, increases in shear stress would only directly activate mitochondria in endothelium through mechanical means as described by Gutterman and colleagues (). Also, focal activation of neurons would impact directly only on the mitochondria in these neurons and lead to NO production, and an appropriate increase in local blood flow.


Figure 1. Electron microscopy section of a small branch of the MCA representative of 10‐ to 12‐week‐old, male Sprague Dawley (SD) rats showing differences in size, morphology, and relationship to other cellular structures of mitochondria in VSM and endothelium. Mitochondria in VSM form large fields with interspersed SR, whereas mitochondria in endothelium seem to be present singly. Rats were euthanized with anesthesia and perfused with a PBS solution containing 2% glutaraldehyde and 3% formaldehyde. Arteries were removed and kept in the perfusion solution for 1 h and post fixed in 1% osmium tetroxide and embedded in Spurr's resin. Ultrathin sections (80–90 nm) were mounted on formvar‐coated copper grids (200 mesh), air dried, and stained with uranyl acetate and lead citrate (at 7 and 7 min, respectively). The sections were put on grids and viewed at a magnification of 11,000× using a FEI Tecnai Bio Twin 120 keV TEM with a digital imaging setup (Wake Forest University Health Sciences, Winston‐Salem, NC). M, mitochondrion; SR, sarcoplasmic reticulum, IEL, internal elastic lamina, VSM, vascular smooth muscle. Magnification is 11,000×.


Figure 2. Electron microscopy section of an MCA representative of 10‐ to 12‐week‐old, female SD rats showing numerous sites of close association of mitochondria in different VSM cells. Several VSM cells with extensive mitochondrial fields are present, and multiple sites of close approximation of adjacent mitochondria are seen. Similar mitochondrial fields and connections in VSM are seen in male arteries. White arrows show examples of close mitochondrial connections. Black arrow shows a stressed mitochondrion. Magnification is 11,000×.


Figure 3. Higher magnification of mitochondrial connections in a VSM cell representative of 10‐ to 12‐week‐old, female SD rats. Numerous apparent contacts between mitochondria (examples shown by white arrows) as well as close approximation of mitochondria and SR. Magnification is 23,000×.


Figure 4. Electron microscopy section of a microvessel in brain parenchyma representative of 10‐ to 12‐week‐old, female SD rats showing a surrounding pericyte with a large mitochondrion as well as mitochondria in astrocytic endfeet. The pericytes and especially astroglial endfeet surround the parenchymal blood vessels and both cell types contain pronounced mitochondria. Magnification is 11,000×. M = mitochondrion, * = astroglial endfoot.


Figure 5. Electron microscopy section of brain parenchyma showing close approximation of microvessel representative of 10‐ to 12‐week‐old, male Zucker lean rats showing glial endfoot with prominent mitochondria. Lean Zucker rats are phenotypically normal and the mitochondria of the cerebral vasculature show no obvious differences with non‐IR rat strains. Magnification 11,000×.


Figure 6. Electron microscopy section of a pial artery representative of 10‐ to 12‐week‐old, male Zucker lean rats showing multiple mitochondria on glia limitans comprising the surface of cerebral cortex as well as in cell layers in adventitial connective tissues and nerves. Fields of mitochondria in astrocytes are shown in the white oval areas and the dashed rectangle corresponds to the area of the section enlarged in Figure . Magnification 1900×.


Figure 7. Higher magnification of indicated section of Figure showing numerous mitochondria in perivascular tissue. White oval shows mitochondrial field in VSM and black oval shows mitochondrial in adventitia. M, mitochondrion, VSM, vascular smooth muscle. Magnification 11,000×.


Figure 8. Electron microscopy section of a MCA representative of 10‐ to 12‐week‐old SD rats showing perivascular innervation. Mitochondria are prominent features in nerve terminals. Myelinated and nonmyelinated nerves are seen associated with the adventitia. M, mitochondrion. Magnification is 30,000×.


Figure 9. Electron microscopy section showing the VSM of a cerebral artery representative of 10‐ to 12‐week‐old, male rats showing damage to mitochondria in VSM at 48 h of reperfusion following 90 min of transient MCA occlusion. Mitochondria appear to be swollen and/or have lost the typical morphology including uniform cristae. Mitochondria in VSM cells following ischemia can have diverse features ranging from a normal appearance or show limited or extensive damage. Nonetheless, dilator responses to sodium nitroprusside, a VSM specific stimulus, are intact following ischemia. Magnification 11,000×.


Figure 10. Schematic illustration showing the primary signaling pathway involving NO production and S6K phosphorylation linking mitochondrial activation with preconditioning of cultured neurons against OGD. (A) All neurons were exposed to OGD. Diazoxide (DZ) protected neurons against OGD. Protection was eliminated by NOS inhibition and restored with NO donors. DZ, diazoxide; SNP, sodium nitroprusside; DEANO, (CH3CH2)2N–N(N=O)O Na+ x H2O. Values are mean ± SEM. *P < 0.05, compared to DZ treated, #P < 0.05, compared with untreated or DZ+L‐NAME treated neurons. Data adapted from (). (B) Preconditioning by neurons was eliminated by coadministration of siRNA against S6K. Values are mean ± SEM, *P < 0.05, compared with DZ preconditioning against OGD. Data adapted from (). (C‐E) Preconditioning by diazoxide enhanced the levels of phosphorylated/total of Akt, mTOR, and S6K and coadministration of L‐NAME reversed this effect during OGD. Values are mean ± SD. DZ, diazoxide, #P < 0.05, compared with no treatment prior to OGD. Data adapted from ().


Figure 11. Demonstration that BMS‐191096 is able to depolarize mitochondria in VSM without eliciting an increase in mitochondrial ROS production. (A) Original tracings showing ESR values for vehicle versus BMS‐191095 and diazoxide for denuded cerebral arteries. (B) ESR analysis showed diazoxide but not BMS‐191095 increased mitochondrial ROS generation in denuded cerebral arteries. (C and D) Original confocal images and summary data showing that diazoxide but not BMS‐191095 increased mitoSOX intensity in VSM. (E and F) Original confocal images and summary data illustrating that BMS‐191095 depolarized (loss of intensity) VSM. Data (means ± SEM) and for graphs and images are from (). *P < 0.05, compared with vehicle.


Figure 12. Schematic illustration showing signaling pathways linking mitochondrial depolarization in different cell types of the neurovascular unit to changes in cerebral vascular tone. The intrinsic VSM response involves mitochondria‐SR interactions resulting in enhanced calcium sparks activity. The extrinsic VSM response involves the effects of vasoactive stimuli such as NO on VSM tone via a cGMP‐linked mechanism. *, phosphorylated state.


Figure 13. Sex dependent differences in mitochondrial dynamics in large cerebral arteries from young rats. (A) Oxygen consumption was greater in 8‐ to 10‐week‐old SD female than male cerebral arteries during treatment with inhibitors of mitochondrial complexes and FCCP. (B) The protein mass of inner mitochondrial membrane proteins such as those composing Complex I were larger in female compared with male cerebral arteries. (C) The protein mass of outer mitochondrial membrane proteins such as those composing VDAC were larger in female compared with male cerebral arteries. (D) Dilation to diazoxide was greater in female compared with male isolated and pressurized MCAs. Data (means ± SEM) are from (). *P < 0.05, compared with male.


Figure 14. Demonstration that transient ischemia reduces dilation of MCAs to acetylcholine, bradykinin, and sodium nitroprusside but not to diazoxide in pressurized, isolated MCAs from 8‐ to 10‐week‐old, male rats. Surprisingly, dilator responses to acetylcholine, bradykinin, and especially diazoxide were reduced in arteries not directly exposed to cessation of blood flow. *P < 0.05, side ipsilateral (IPSI) to stroke compared with sham control, P < 0.05, IPSI compared to sham control, P < 0.05, compared to contralateral side (CONTRA). Data (means ± SEM) adapted from ().


Figure 15. Retained dilation of pressurized, isolated MCAs from 8‐ to 10‐week‐old, male rats following ischemia is due to mitochondrial activation in endothelium and not VSM. (A) Approximately one‐half of all dilation to diazoxide in Sham, control MCAs is due to endothelial factors while the remainder is due to VSM. In contrast, the retained dilation following ischemia in MCAs is due solely to endothelium. Denudation reduced dilation more in Sham than Ipsi arteries. (B) Phosphorylation of eNOS is greater in previously ischemic MCAs, which is consistent with a greater endothelial contribution to the retained dilation. *P < 0.05, compared with Sham. (C) Calcium sparks activity during basal conditions is reduced in previously ischemic MCAs and does not increase substantially in the presence of diazoxide. Unpublished data (means ± SEM) for panel C were generated using previously published methods () from MCA of male SD rats 48 h after 90 min of ischemia. IPSI represents artery that was occluded and Sham represents a corresponding MCA that was not ischemic from a Sham operated rat. *P < 0.05, compared with Sham. n = 14 images for Sham and Ipsi arteries. (D) Representative electron microscopic image shows areas of VSM where mitochondrial damage is apparent which accounts for decreased calcium sparks activity. Data (means ± SEM) for A and B are from ().


Figure 16. Schematic illustration of mitochondrial influences on cell types within the neurovascular unit. All cell types within the neurovascular unit are capable of affecting cerebral vascular tone through their mitochondrial mechanisms. Although the majority of mitochondria in the neurovascular unit can be simultaneously affected by insults such as ischemia or cortical spreading depression, it is more likely that only limited populations of mitochondrial are activated during changes in physiological status. For example, increases in shear stress would only directly activate mitochondria in endothelium through mechanical means as described by Gutterman and colleagues (). Also, focal activation of neurons would impact directly only on the mitochondria in these neurons and lead to NO production, and an appropriate increase in local blood flow.
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David W. Busija, Ibolya Rutkai, Somhrita Dutta, Prasad V. Katakam. Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone. Compr Physiol 2016, 6: 1529-1548. doi: 10.1002/cphy.c150051