| 1. |
- Cseplo, Peter, et al.
(författare)
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Hemolyzed Blood Elicits a Calcium Antagonist and High CO2 Reversible Constriction via Elevation of [Ca2+]i in Isolated Cerebral Arteries
- 2017
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 34:2, s. 529-534
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Tidskriftsartikel (refereegranskat)abstract
- During acute subarachnoid hemorrhage, blood is hemolyzed, which is followed by a significant cerebrovascular spasm resulting in a serious clinical condition. Interestingly, however, the direct vasomotor effect of perivascular hemolyzed blood (HB) has not yet been characterized, preventing the assessment of contribution of vasoconstrictor mechanisms deriving from brain tissue and/or blood and development of possible treatments. We hypothesized that perivascular HB reduces the diameter of the cerebral arteries (i.e., basilar artery [BA]; middle cerebral artery [MCA]) by elevating vascular tissue [Ca2+](i) level. Vasomotor responses were measured by videomicroscopy and intracellular Ca2+ by the Fura2-AM ratiometric method. Adding HB to the vessel chamber reduced the diameter significantly (BA: from 264 +/- 7 to 164 +/- 11 mu m; MCA: from 185 +/- 15 to 155 +/- 14 mu m), which was reversed to control level by wash-out of HB. Potassium chloride (KCl), HB, serum, hemolyzed red blood cell (RBC), plasma, and platelet suspension (PLTs) elicited significant constrictions of isolated basilar arteries. There was a significant increase in K+ concentration in hemolyzed HB (7.02 +/- 0.22 mmol/L) compared to Krebs' solution (6.20 +/- 0.01 mmol/L). Before HB, acetylcholine (ACh), sodium-nitroprussid (SNP), nifedipin, and CO2 elicited substantial dilations in cerebral arteries. In contrast, in the presence of HB dilations to ACh, SNP decreased, but not to nifedipine and CO2. After washout of HB, nitric oxide-mediated dilations remained significantly reduced compared to control. HB significantly increased the ratiometric Ca signal, which returned to control level after washout. In conclusion, perivascular hemolyzed blood elicits significant-nifedipine and high CO2 reversible-constrictions of isolated BAs and MCAs, primarily by increasing intracellular Ca2+, findings that can contribute to the refinement of local treatment of subarachnoid hemorrhage.
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| 2. |
- Czigler, Andras, et al.
(författare)
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Hypertension exacerbates cerebrovascular oxidative stress induced by mild traumatic brain injury : Protective effects of the Mitochondria-Targeted Antioxidative Peptide SS-31
- 2019
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 36:23, s. 3309-3315
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) induces cerebrovascular oxidative stress, which is associated with neurovascular uncoupling, autoregulatory dysfunction, and persisting cognitive decline in both pre-clinical models and patients. However, single mild TBI (mTBI), the most frequent form of brain trauma, increases cerebral generation of reactive oxygen species (ROS) only transiently. We hypothesized that comorbid conditions might exacerbate long-term ROS generation in cerebral arteries after mTBI. Because hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive and spontaneously hypertensive rats (SHR) and assessed changes in cytoplasmic and mitochondrial superoxide (O2-) production by confocal microscopy in isolated middle cerebral arteries (MCA) 2 weeks after mTBI using dihydroethidine (DHE) and the mitochondria-targeted redox-sensitive fluorescent indicator dye MitoSox. We found that mTBI induced a significant increase in long-term cytoplasmic and mitochondrial O2- production in MCAs of SHRs and increased expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit Nox4, which were reversed to the normal level by treating the animals with the cell-permeable, mitochondria-targeted antioxidant peptide SS-31 (5.7 mg kg-1 day-1, i.p.). Persistent mTBI-induced oxidative stress in MCAs of SHRs was significantly decreased by inhibiting vascular NADPH oxidase (apocyinin). We propose that hypertension- and mTBI-induced cerebrovascular oxidative stress likely lead to persistent dysregulation of cerebral blood flow (CBF) and cognitive dysfunction, which might be reversed by SS-31 treatment.
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| 3. |
- Czigler, Andras, et al.
(författare)
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Prostaglandin E2, a postulated mediator of neurovascular coupling, at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles
- 2020
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Ingår i: Prostaglandins & other lipid mediators. - : Elsevier. - 1098-8823 .- 2212-196X. ; 146
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Tidskriftsartikel (refereegranskat)abstract
- There is considerable controversy regarding the vasoactive action of prostaglandin E2 (PGE2). On the one hand, indirect evidence implicates that astrocytic release of PGE2 contributes to neurovascular coupling responses mediating functional hyperemia in the brain. On the other hand, overproduction of PGE2 was also reported to contribute to cerebral vasospasm associated with subarachnoid hemorrhage. The present study was conducted to resolve this controversy by determining the direct vasoactive effects of PGE2 in resistance-sized human cerebral parenchymal arterioles. To achieve this goal PGE2-induced isotonic vasomotor responses were assessed in parenchymal arterioles isolated from fronto-temporo-parietal cortical tissues surgically removed from patients and expression of PGE2 receptors were examined. In functionally intact parenchymal arterioles lower concentrations of PGE2 (from 10-8 to 10-6 mol/l) caused significant, endothelium-independent vasorelaxation, which was inhibited by the EP4 receptor blocker BGC201531. In contrast, higher concentrations of PGE2 evoked significant EP1-dependent vasoconstriction, which could not be reversed by the EP4 receptor agonist CAY10598. We also confirmed previous observations that PGE2 primarily evokes constriction in intracerebral arterioles isolated from R. norvegicus. Importantly, vascular mRNA and protein expression of vasodilator EP4 receptors was significantly higher than that of vasoconstrictor EP1 receptors in human cerebral arterioles. PGE2 at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles. This bimodal vasomotor response is consistent with both the proposed vasodilator role of PGE2 during functional hyperemia and its putative role in cerebral vasospasm associated with subarachnoid hemorrhage in human patients.
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| 4. |
- Szarka, Nikolett, et al.
(författare)
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Hypertension-Induced Enhanced Myogenic Constriction of Cerebral Arteries Is Preserved after Traumatic Brain Injury
- 2017
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 34:14, s. 2315-2319
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) was shown to impair pressure-induced myogenic response of cerebral arteries, which is associated with vascular and neural dysfunction and increased mortality of TBI patients. Hypertension was shown to enhance myogenic tone of cerebral arteries via increased vascular production of 20-hydroxyeicosatrienoic acid (HETE). This adaptive mechanism protects brain tissue from pressure/volume overload; however, it can also lead to increased susceptibility to cerebral ischemia. Although both effects may potentiate the detrimental vascular consequences of TBI, it is not known how hypertension modulates the effect of TBI on myogenic responses of cerebral vessels. We hypothesized that in hypertensive rats, the enhanced myogenic cerebrovascular response is preserved after TBI. Therefore, we investigated the myogenic responses of isolated middle cerebral arteries (MCA) of normotensive and spontaneously hypertensive rats (SHR) after severe impact acceleration diffuse brain injury. TBI diminished myogenic constriction of MCAs isolated from normotensive rats, whereas the 20-HETE-mediated enhanced myogenic response of MCAs isolated from SHRs was not affected by TBI. These results suggest that the optimal cerebral perfusion pressure values and vascular signaling pathways can be different and, therefore, should be targeted differently in normotensive and hypertensive patients following TBI.
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| 5. |
- Szarka, Nikolett, et al.
(författare)
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Single mild traumatic brain injury induces persistent disruption of the blood-brain barrier, neuroinflammation and ognitive decline in hypertensive rats
- 2019
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 20:13, s. 3223-3223
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) induces blood-brain barrier (BBB) disruption, which contributes to secondary injury of brain tissue and development of chronic cognitive decline. However, single mild (m)TBI, the most frequent form of brain trauma disrupts the BBB only transiently. We hypothesized, that co-morbid conditions exacerbate persistent BBB disruption after mTBI leading to long term cognitive dysfunction. Since hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive Wistar and spontaneously hypertensive rats (SHR) and we assessed BBB permeability, extravasation of blood-borne substances, neuroinflammation and cognitive function two weeks after trauma. We found that mTBI induced a significant BBB disruption two weeks after trauma in SHRs but not in normotensive Wistar rats, which was associated with a significant accumulation of fibrin and increased neuronal expression of inflammatory cytokines TNFα, IL-1β and IL-6 in the cortex and hippocampus. SHRs showed impaired learning and memory two weeks after mild TBI, whereas cognitive function of normotensive Wistar rats remained intact. Future studies should establish the mechanisms through which hypertension and mild TBI interact to promote persistent BBB disruption, neuroinflammation and cognitive decline to provide neuroprotection and improve cognitive function in patients with mTBI.
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| 6. |
- Szarka, Nikolett, et al.
(författare)
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Traumatic brain injury impairs myogenic constriction of cerebral arteries : role of mitochondria-derived H2O2 and TRPV4-dependent activation of BKca Channels
- 2018
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 35:7, s. 930-939
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) impairs autoregulation of cerebral blood flow, which contributes to the development of secondary brain injury, increasing mortality of patients. Impairment of pressure-induced myogenic constriction of cerebral arteries plays a critical role in autoregulatory dysfunction; however, the underlying cellular and molecular mechanisms are not well understood. To determine the role of mitochondria-derived H2O2 and large-conductance calcium-activated potassium channels (BKCa) in myogenic autoregulatory dysfunction, middle cerebral arteries (MCAs) were isolated from rats with severe weight drop-impact acceleration brain injury. We found that 24 h post-TBI MCAs exhibited impaired myogenic constriction, which was restored by treatment with a mitochondria-targeted antioxidant (mitoTEMPO), by scavenging of H2O2 (polyethylene glycol [PEG]-catalase) and by blocking both BKCa channels (paxilline) and transient receptor potential cation channel subfamily V member 4 (TRPV4) channels (HC 067047). Further, exogenous administration of H2O2 elicited significant dilation of MCAs, which was inhibited by blocking either BKCa or TRPV4 channels. Vasodilation induced by the TRPV4 agonist GSK1016790A was inhibited by paxilline. In cultured vascular smooth muscle cells H2O2 activated BKCa currents, which were inhibited by blockade of TRPV4 channels. Collectively, our results suggest that after TBI, excessive mitochondria-derived H2O2 activates BKCa channels via a TRPV4-dependent pathway in the vascular smooth muscle cells, which impairs pressure-induced constriction of cerebral arteries. Future studies should elucidate the therapeutic potential of pharmacological targeting of this pathway in TBI, to restore autoregulatory function in order to prevent secondary brain damage and decrease mortality.
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| 7. |
- Toth, Luca, et al.
(författare)
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Age-related decline in circulating IGF-1 associates with impaired neurovascular coupling responses in older adults
- 2022
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Ingår i: GeroScience. - : Springer. - 2509-2715 .- 2509-2723. ; 44:6, s. 2771-2783
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Tidskriftsartikel (refereegranskat)abstract
- Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) to the increased oxygen and energy requirements of active brain regions via neurovascular coupling (NVC) contributes to the genesis of age-related cognitive impairment. Aging is associated with marked deficiency in the vasoprotective hormone insulin-like growth factor-1 (IGF-1). Preclinical studies on animal models of aging suggest that circulating IGF-1 deficiency is causally linked to impairment of NVC responses. The present study was designed to test the hypotheses that decreases in circulating IGF-1 levels in older adults also predict the magnitude of age-related decline of NVC responses. In a single-center cross-sectional study, we enrolled healthy young (n = 31, 11 female, 20 male, mean age: 28.4 + / - 4.2 years) and aged volunteers (n = 32, 18 female, 14 male, mean age: 67.9 + / - 4.1 years). Serum IGF-1 level, basal CBF (phase contrast magnetic resonance imaging (MRI)), and NVC responses during the trail making task (with transcranial Doppler sonography) were assessed. We found that circulating IGF-1 levels were significantly decreased with age and associated with decreased basal CBF. Age-related decline in IGF-1 levels predicted the magnitude of age-related decline in NVC responses. In conclusion, our study provides additional evidence in support of the concept that age-related circulating IGF-1 deficiency contributes to neurovascular aging, impairing CBF and functional hyperemia in older adults.
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| 8. |
- Toth, Peter, et al.
(författare)
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Traumatic brain injury-induced autoregulatory dysfunction and spreading depression-related neurovascular uncoupling : Pathomechanisms, perspectives, and therapeutic implications
- 2016
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Ingår i: American Journal of Physiology. - : HighWire Press. - 0002-9513 .- 2163-5773. ; 311:5, s. H1118-H1131
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Forskningsöversikt (refereegranskat)abstract
- Traumatic brain injury (TBI) is a major health problem worldwide. In addition to its high mortality (35-40%), survivors are left with cognitive, behavioral, and communicative disabilities. While little can be done to reverse initial primary brain damage caused by trauma, the secondary injury of cerebral tissue due to cerebro-microvascular alterations and dysregulation of cerebral blood flow (CBF) is potentially preventable. This review focuses on functional, cellular, and molecular changes of autoregulatory function of CBF (with special focus on cerebrovascular myogenic response) that occur in cerebral circulation after TBI and explores the links between autoregulatory dysfunction, impaired myogenic response, microvascular impairment, and the development of secondary brain damage. We further provide a synthesized translational view of molecular and cellular mechanisms involved in cortical spreading depolarization-related neurovascular dysfunction, which could be targeted for the prevention or amelioration of TBI-induced secondary brain damage.
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