TY - JOUR AU - Szarka, Nikolett AU - Pabbidi, MR AU - Amrein, Krisztina AU - Czeiter, Endre AU - Berta, Gergely AU - Pohóczky, Krisztina AU - Helyes, Zsuzsanna AU - Ungvári, Zoltán István AU - Koller, Ákos AU - Büki, András AU - Tóth, Péter József TI - Traumatic brain injury impairs myogenic constriction of cerebral arteries: role of mitochondria-derived H2O2 and TRPV4-dependent activation of BKCa channels JF - JOURNAL OF NEUROTRAUMA J2 - J NEUROTRAUM VL - 35 PY - 2018 IS - 7 SP - 930 EP - 939 PG - 10 SN - 0897-7151 DO - 10.1089/neu.2017.5056 UR - https://m2.mtmt.hu/api/publication/3297273 ID - 3297273 AB - 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 (24 h post-impact). We found that post-TBI MCAs exhibited impaired myogenic constriction, which was restored by treatment with a mitochondria-targeted antioxidant (mitoTEMPO), by scavenging of H2O2 (PEG-catalase) and by blocking both BKCa channels (paxilline) and TRPV4 channels (HC067047). 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. LA - English DB - MTMT ER - TY - JOUR AU - Tarantini, Stefano AU - Valcarcel-Ares, NM AU - Yabluchanskiy, A AU - Fülöp, Gábor Áron AU - Hertelendy, Péter AU - Gautam, T AU - Farkas, Eszter AU - Perz, A AU - Rabinovitch, PS AU - Sonntag, WE AU - Csiszar, Anna AU - Ungvári, Zoltán István TI - Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice JF - AGING CELL J2 - AGING CELL VL - 17 ET - 0 PY - 2018 IS - 2 PG - 12 SN - 1474-9718 DO - 10.1111/acel.12731 UR - https://m2.mtmt.hu/api/publication/3367042 ID - 3367042 N1 - * Megosztott szerzőség LA - English DB - MTMT ER - TY - JOUR AU - Szarka, Nikolett AU - Amrein, Krisztina AU - Horváth, Péter AU - Ivic, Ivan AU - Czeiter, Endre AU - Büki, András AU - Koller, Ákos AU - Tóth, Péter József TI - HYPERTENSION-INDUCED ENHANCED MYOGENIC CONSTRICTION OF CEREBRAL ARTERIES IS PRESERVED AFTER TRAUMATIC BRAIN INJURY. JF - JOURNAL OF NEUROTRAUMA J2 - J NEUROTRAUM VL - 34 PY - 2017 IS - 14 SP - 2315 EP - 2319 PG - 5 SN - 0897-7151 DO - 10.1089/neu.2016.4962 UR - https://m2.mtmt.hu/api/publication/3195505 ID - 3195505 AB - 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 form pressure/volume overload, but 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. Thus, 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 thus should be targeted differently in normotensive and hypertensive patients following TBI. LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Péter József AU - Szarka, Nikolett AU - Farkas, Eszter AU - Ezer, Erzsébet AU - Czeiter, Endre AU - Amrein, Krisztina AU - Ungvári, Zoltán István AU - Hartings, JA AU - Büki, András AU - Koller, Ákos TI - Traumatic brain injury-induced autoregulatory dysfunction and spreading depression-related neurovascular uncoupling: Pathomechanisms, perspectives, and therapeutic implications JF - AMERICAN JOURNAL OF PHYSIOLOGY: HEART AND CIRCULATORY PHYSIOLOGY J2 - AM J PHYSIOL HEART C VL - 311 PY - 2016 IS - 5 SP - H1118 EP - H1131 PG - 14 SN - 0363-6135 DO - 10.1152/ajpheart.00267.2016 UR - https://m2.mtmt.hu/api/publication/3110623 ID - 3110623 LA - English DB - MTMT ER - TY - JOUR AU - Springó, Zsolt AU - Tarantini, Stefano AU - Tóth, Péter József AU - Tucsek, Z AU - Koller, Ákos AU - Sonntag, WE AU - Csiszar, Anna AU - Ungvári, Zoltán István TI - Aging exacerbates pressure-induced mitochondrial oxidative stress in mouse cerebral arteries JF - JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES J2 - J GERONTOL A-BIOL MED SCI VL - 70 PY - 2015 IS - 11 SP - 1355 EP - 1359 PG - 5 SN - 1079-5006 DO - 10.1093/gerona/glu244 UR - https://m2.mtmt.hu/api/publication/2798902 ID - 2798902 AB - Epidemiological studies demonstrate that in addition to the increased prevalence of hypertension in old patients, the deleterious cerebrovascular effects of hypertension ( including atherosclerosis, stroke, and vascular cognitive impairment) are also exacerbated in elderly individuals. The cellular mechanisms by which aging and hypertension interact to promote cerebrovascular pathologies are not well understood. To test the hypothesis that aging exacerbates high pressure-induced mitochondrial oxidative stress, we exposed isolated segments of the middle cerebral arteries of young ( 3 months) and aged ( 24 months) C57BL/6 mice to 60 or 140 mmHg intraluminal pressure and assessed changes in mitochondrial reactive oxygen species production using a mitochondria-targeted redox-sensitive fluorescent indicator dye ( MitoSox) by confocal microscopy. Perinuclear MitoSox fluorescence was significantly stronger in high pressure-exposed middle cerebral arteries compared with middle cerebral arteries of the same animals exposed to 60 mmHg, indicating that high pressure increases mitochondrial reactive oxygen species production in the smooth muscle cells of cerebral arteries. Comparison of young and aged middle cerebral arteries showed that aging exacerbates high pressure-induced mitochondrial reactive oxygen species production in cerebral arteries. We propose that increased mechanosensitive mitochondrial oxidative stress may potentially exacerbate cerebrovascular injury and vascular inflammation in aging. LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Péter József AU - Tarantini, Stefano AU - Tucsek, Zsuzsanna AU - Ashpole, NM AU - Sosnowska, D AU - Gautam, T AU - Ballabh, P AU - Koller, Ákos AU - Sonntag, WE AU - Csiszar, Anna AU - Ungvári, Zoltán István TI - Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase JF - AMERICAN JOURNAL OF PHYSIOLOGY: HEART AND CIRCULATORY PHYSIOLOGY J2 - AM J PHYSIOL HEART C VL - 306 PY - 2014 IS - 3 SP - H299 EP - H308 PG - 10 SN - 0363-6135 DO - 10.1152/ajpheart.00744.2013 UR - https://m2.mtmt.hu/api/publication/2496231 ID - 2496231 AB - Moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is essential for the maintenance of normal neuronal function. Increased oxidative stress that occurs with aging was shown to impair neurovascular coupling, which likely contributes to a significant age-related decline in higher brain function, increasing the risk for vascular cognitive impairment (VCI). Resveratrol is a polyphenolic compound that exerts significant anti-aging protective effects in large vessels but its effects on the cerebromicrovasculature remain poorly defined. The present study was undertaken to investigate the capacity of resveratrol to improve neurovascular coupling in aging. In aged (24 months old) C57BL/6 mice L-NAME sensitive, NO-mediated CBF responses to whisker stimulation and to the endothelium-dependent dilator acethylcholine (ACh) were impaired as compared to those in young (3 months old) mice. Treatment of aged mice with resveratrol rescued neurovascular coupling and ACh-induced responses, which was associated with down-regulation of cortical expression of NADPH oxidase and decreased levels of biomarkers of oxidative/nitrative stress (3-nitrotyrosine, 8-isoprostanes). Resveratrol also attenuated age-related increases in ROS production in cultured cerebromicrovascular endothelial cells (DCF fluorescence, flow cytometry). In conclusion, treatment with resveratrol rescues cortical neurovascular coupling responses to increased neuronal activity in aged mice, likely by restoring cerebromicrovascular endothelial function via down-regulation of NADPH-oxidase derived ROS production. Beneficial cerebromicrovascular effects of resveratrol likely contribute to its protective effects on higher brain function in aging. LA - English DB - MTMT ER - TY - JOUR AU - Dikalov, SI AU - Ungvári, Zoltán István TI - Role of mitochondrial oxidative stress in hypertension JF - AMERICAN JOURNAL OF PHYSIOLOGY: HEART AND CIRCULATORY PHYSIOLOGY J2 - AM J PHYSIOL HEART C VL - 305 PY - 2013 IS - 10 SP - H1417 EP - H1427 SN - 0363-6135 DO - 10.1152/ajpheart.00089.2013 UR - https://m2.mtmt.hu/api/publication/2528667 ID - 2528667 LA - English DB - MTMT ER - TY - JOUR AU - Dai, DF AU - Rabinovitch, PS AU - Ungvári, Zoltán István TI - Mitochondria and Cardiovascular Aging JF - CIRCULATION RESEARCH J2 - CIRC RES VL - 110 PY - 2012 IS - 8 SP - 1109 EP - 1124 PG - 16 SN - 0009-7330 DO - 10.1161/CIRCRESAHA.111.246140 UR - https://m2.mtmt.hu/api/publication/2528682 ID - 2528682 LA - English DB - MTMT ER - TY - JOUR AU - Csiszar, Anna AU - Labinskyy, N AU - Perez, V AU - Recchia, FA AU - Podlutsky, A AU - Mukhopadhyay, P AU - Losonczy, György AU - Pacher, Pál AU - Austad, SN AU - Bartke, A AU - Ungvári, Zoltán István TI - Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice JF - AMERICAN JOURNAL OF PHYSIOLOGY: HEART AND CIRCULATORY PHYSIOLOGY J2 - AM J PHYSIOL HEART C VL - 295 PY - 2008 IS - 5 SP - H1882 EP - H1894 SN - 0363-6135 DO - 10.1152/ajpheart.412.2008 UR - https://m2.mtmt.hu/api/publication/1416573 ID - 1416573 AB - Csiszar A, Labinskyy N, Perez V, Recchia FA, Podlutsky A, Mukhopadhyay P, Losonczy G, Pacher P, Austad SN, Bartke A, Ungvari Z. Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice. Am J Physiol Heart Circ Physiol 295: H1882-H1894, 2008. First published August 29, 2008; doi:10.1152/ajpheart.412.2008. - Hypopituitary Ames dwarf mice have low circulating growth hormone (GH)/IGF-I levels, and they have extended longevity and exhibit many symptoms of delayed aging. To elucidate the vascular consequences of Ames dwarfism we compared endothelial O-2(center dot-) and H2O2 production, mitochondrial reactive oxygen species (ROS) generation, expression of antioxidant enzymes, and nitric oxide (NO) production in aortas of Ames dwarf and wild-type control mice. In Ames dwarf aortas endothelial O-2(center dot-) and H2O2 production and ROS generation by mitochondria were enhanced compared with those in vessels of wild-type mice. In Ames dwarf aortas there was a less abundant expression of Mn-SOD, Cu, Zn-SOD, glutathione peroxidase (GPx)-1, and endothelial nitric oxide synthase (eNOS). NO production and acetylcholine-induced relaxation were also decreased in aortas of Ames dwarf mice. In cultured wild-type mouse aortas and in human coronary arterial endothelial cells treatment with GH and IGF significantly reduced cellular O-2(center dot-) and H2O2 production and ROS generation by mitochondria and upregulated expression of Mn-SOD, Cu, Zn-SOD, GPx-1, and eNOS. Thus GH and IGF-I promote antioxidant phenotypic changes in the endothelial cells, whereas Ames dwarfism leads to vascular oxidative stress. LA - English DB - MTMT ER - TY - JOUR AU - Hortobagyi, L AU - Kis, B AU - Hrabák, András AU - Horváth, Béla András AU - Huszty, Gergely AU - Schweer, H AU - Benyó, Balázs István AU - Sándor, Péter AU - Busija, DW AU - Benyó, Zoltán TI - Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids JF - BRAIN RESEARCH J2 - BRAIN RES VL - 1131 PY - 2007 SP - 129 EP - 137 PG - 9 SN - 0006-8993 DO - 10.1016/j.brainres.2006.11.009 UR - https://m2.mtmt.hu/api/publication/1151559 ID - 1151559 LA - English DB - MTMT ER -