The role of transient receptor potential channels in cerebral myogenic autoregulation in hypertension and aging
2020; American Physical Society; Volume: 319; Issue: 1 Linguagem: Inglês
10.1152/ajpheart.00403.2020
ISSN1522-1539
AutoresLuca Tóth, András Czigler, Nikolett Szarka, Péter Tóth,
Tópico(s)S100 Proteins and Annexins
ResumoEditorial FocusThe role of transient receptor potential channels in cerebral myogenic autoregulation in hypertension and agingLuca Toth, Andras Czigler, Nikolett Szarka, and Peter TothLuca TothDepartment of Neurosurgery, Medical School, University of Pecs, Hungary, Andras CziglerDepartment of Neurosurgery, Medical School, University of Pecs, Hungary, Nikolett SzarkaDepartment of Translational Medicine, Medical School, University of Pecs, Hungary, and Peter TothDepartment of Neurosurgery, Medical School, University of Pecs, HungaryDepartment of Translational Medicine, Medical School, University of Pecs, HungaryMTA-PTE Clinical Neuroscience MR Research Group of the Hungarian Academy of Sciences, Pecs, HungaryInternational Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, HungaryPublished Online:02 Jul 2020https://doi.org/10.1152/ajpheart.00403.2020This is the final version - click for previous versionMoreSectionsPDF (742 KB)Download PDFDownload PDFPlus ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmail Regulation of the cerebral circulation has to comply with unique conditions. Cerebral tissue does not have sufficient energy stores; therefore, stable blood flow has to be provided for normal metabolism, even in cases of abnormally decreased blood pressure. On the other hand, in the face of increasing blood pressure, cerebral blood flow (CBF) cannot increase as a function of pressure, because it would lead to hyperperfusion and thus increased blood volume in the closed skull. This hydrostatic overload could result in increased intracranial pressure and injury to the thin-walled brain capillaries, leading to disruption of the blood-brain barrier and formation of cerebral edema and hemorrhages, which would further elevate intracranial pressure, closing a vicious cycle (9). These pathophysiological conditions are prevented by a mechanism called autoregulation of cerebral blood flow. By adjusting cerebrovascular resistance (CVR), autoregulation renders cerebral blood flow independent from changes in blood pressure. When autoregulation is defined as the mechanism that maintains constant CBF despite changes in blood pressure in a negative feedback manner, autoregulation is mainly due to the pressure-induced, myogenic response of cerebral arteries and arterioles. Accordingly, in a simplistic model, in case of hypotension, cerebral resistance vessels dilate and CVR decreases to prevent hypoperfusion of cerebral tissue. In case of hypertension, vasoconstriction and consequent increase in CVR maintain nearly normal blood flow and protect the microcirculation from pressure and volume overload. As mentioned above, lack of these protective mechanisms (in case of autoregulatory dysfunction) plays a central role in various pathological conditions, i.e., hypertensive encephalopathy, preeclampsia, traumatic brain injury, etc. (7).In chronic hypertension, cerebrovascular resistance is elevated not only because of remodeling of the cerebrovascular wall but also because increased myogenic constriction of cerebral arteries. Because of increased CVR, patients with hypertension and hypertensive laboratory animals maintain a normal CBF in absolute values despite the enhanced blood pressure (this is the basis of the so-called "rightward shift of the autoregulatory curve") (7) (Fig. 1). This adaptive response protects the microcirculation from the damaging effect of high pressure. A few years ago, it was demonstrated that augmented myogenic constriction and therefore extension of the autoregulated pressure range of middle cerebral arteries (MCAs) of rats with angiotensin II-induced hypertension in response to high intraluminal pressure (160 mmHg) were mediated by the activation of transient receptor potential canonical channels 6 (TRPC6) (6, 8) (Fig. 1). TRPC6 channels are nonselective cation channels from the TRP ion channel superfamily, which when activated by wall stretch (due to increased intraluminal pressure), leads to depolarization of smooth muscle cell (SMC) membrane, opening of voltage-gated Ca2+ channels, increase in intracellular Ca2+ concentration ([Ca2+]i), and consequent constriction of SMCs (1). Accordingly, it was shown that angiotensin II-induced hypertension upregulated the expression of trpc6 in rat MCAs and that 160 mmHg-induced enhanced constriction of the vessels along with the augmented increase in [Ca2+]i of SMCs were restored to the control level in the presence of the nonselective inhibitor SKF96365. Interestingly, TRPC6 channels were activated by the arachidonic acid metabolite 20-hydroxyeicosatrienoic acid (20-HETE), the production of which was also induced by chronic angiotensin II-induced hypertension (6, 9) (Fig. 1). TRPC channel activation distally from the production of 20-HETE suggests that TRPC channels were involved in the mediation of the enhanced myogenic constriction of cerebral arteries and not in sensing intraluminal pressure. Importantly, these studies demonstrated that this TRPC6-dependent adaptive enhancement of the myogenic response of cerebral arteries and protective extension of CBF autoregulation to high pressure values are absent in aged hypertensive rats (6, 9). Twenty-four-month-old rats with angiotensin II-induced hypertension failed to upregulate expression and function of the 20-HETE-TRPC6 pathway and did not exhibit an increased myogenic constriction in response to high pressure, which was associated with downstream damage of the microcirculation. Namely, disruption of the blood-brain barrier and neuroinflammation were demonstrated in the brains of aged hypertensive rats with autoregulatory dysfunction, which were associated with cognitive deficit of these animals (6, 9) (Fig. 1). Importantly, one of the major limitations of these studies was the use of the nonselective TRP channel inhibitor SKF96365, and therefore only indirect evidence suggested the involvement of TRPC6 channels in the mentioned processes.Fig. 1.The proposed effect of hypertension and aging on myogenic constriction of cerebral arteries and autoregulation of cerebral blood flow (CBF). Chronic hypertension leads to the increased expression of the 20-hydroxyeicoastrienoic acid (20-HETE) producing cytochrome-P450 enzymes (CYP 450 4A) and transient receptor potential canonical 6 channels (TRPC6) in cerebral arteries. In response to high intraluminal pressure, increased amount of 20-HETE is produced and activates TRPC6 channels, which lead to a sustained constriction of cerebral arteries via an augmented increase in SMC Ca2+ content. The effects of other transient receptor potential channels [TRPC3 and transient receptor potential cation channel subfamily M member 4 (TRPM4)] on the activation of TRPC6 and the pressure-induced Ca2+ signaling in smooth muscle cells of cerebral arteries and arterioles of hypertensive laboratory animals and patients are not known and needs to be established in the future. The sustained constriction of cerebral arteries in response to high intraluminal pressure results in increased cerebrovascular resistance; therefore, hypertensive animals maintain a nearly unchanged cerebral blood flow despite their increased blood pressure values. This adaptive rightward shift of the upper limit of CBF autoregulation protects the cerebral microcirculation from the damaging effect of high intraluminal pressure and volume. Importantly, in aging, the sustained myogenic constriction of cerebral arteries cannot be observed in response to high intraluminal pressure, because chronic hypertension fails to upregulate and overactivate the 20-HETE-TRPC6 pathway. It was demonstrated that age-related endocrine changes, specifically the decreased level of circulating insulin-like growth factor-1 (IGF-1), play an important role in this maladaptive vasoregulatory mechanism, but the effect of IGF-1 deficiency on TRPC and other ion channels involved needs future investigation. Lack of increased myogenic constriction of cerebral arteries of aged hypertensive rats to high intraluminal pressure results in a maladaptive autoregulatory function, which cannot maintain near normal CBF despite high blood pressure of the animals, resulting in hydrostatic overload of the cerebral microcirculation and consequent disruption of the blood-brain barrier (BBB), formation of cerebral edema, and hemorrhages, all of which lead to compromised neuronal function. AA, arachidonic acid.Download figureDownload PowerPointIn this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Nemeth et al. (5) tested the role of TRPC6 channels in myogenic responses of MCAs isolated from wild-type and TRPC6 knockout mice and elegantly demonstrated that in the absence of TRPC channels, increases in pressure did not evoke a constrictor response of the MCAs. These results provide direct evidence that TRPC6 contributes to the myogenic constriction of cerebral arteries of mice, whereas agonist-induced constrictor and dilator responses of MCAs were not impaired, suggesting that the vessels were functionally intact. However, it cannot be excluded that other ion channels compensated or modified the lacking effect of TRPC6. For example, TRPC6 forms heterotrimeric complexes with TRPC3 and TRPC7 channels, whose expression and function should be tested in the presented model. Especially, that expression and function of constrictor TRPC3 channels have been shown to be enhanced in the absence of TRPC6 channels, and its expression in cerebral arteries of C57BL6 mice was not upregulated in hypertension (2). An important point would be to establish the role of transient receptor potential channel melastatin subfamily 4 (TRPM4) in the observed responses. Very well-controlled studies suggested that TRPM4 contributes to the myogenic response of cerebral arteries. Although lack of TRPC6 practically abolished the myogenic constriction of MCAs, suggesting the sole role of these channels in the pressure induced responses, it was previously shown that inhibition of either TRPC6 and TRPM4 leads to similar attenuation of the myogenic response, indicating an interaction between the two channels (3). It was proposed that Ca2+ entry following stretch-related opening of TRPC6 channels would activate TRPM4 channels, leading to Na+ entry into SMCs, depolarization, opening of voltage-gated Ca2+ channels, and consequent constriction (3). TRPC6 channels are sensitive to wall stretch and are ideal candidates to sense changes in intraluminal pressure. This important possibility needs further testing, especially that in hypertension the activation of TRPC6 channels seems to be dependent on 20-HETE. This suggest that TRPC6 channels are distal to the production of 20-HETE (6, 8). Verifying this could provide a more specified therapeutical targeting of the pathological vasomotor responses of the vessels via dissecting the effect of 20-HETE and TRPC6 channels.The role of TRPC6 channels in hypertension-induced enhanced myogenic constriction of cerebral arteries and in vivo extension of CBF autoregulation were shown to be associated, but the causal relationship has not been established (6, 8). Therefore, it would be important to study in vivo autoregulatory function in TRPC knockout mice to demonstrate the role of the channels in CBF autoregulation in addition to the demonstrated role in local vasoregulatory mechanisms. We propose that autoregulation of CBF will be impaired in mice lacking TRPC6 function and that pharmacologically induced hypertension would result in the distal injury of the cerebral microcirculation, i.e., BBB disruption and formation of cerebral microhemorrhages, in these animals, mimicking the aging phenotype. This hypothesis needs future testing.An important point is the effect of age-related neuroendocrine factors on regulation of cerebral blood flow both in physiological and pathophysiological conditions. Insulin-like growth factor 1 (IGF-1) declines with age. We found that mimicking the aging phenotype, impaired adaptation of autoregulation of CBF to hypertension was a result of lack of hepatic production of IGF-1 after viral knockdown in mice (10). Accordingly, upregulation of TRPC6 channels was absent in MCAs of IGF-1 KO animals, and enhanced myogenic constriction in response to high intraluminal pressure was reversed to the control level. This impaired adaptation of autoregulatory function to hypertension resulted in downstream development of BBB disruption, formation of cerebral microhemorrhages, neuroinflammation, and cognitive decline in these mice (10). The mechanisms by which IGF-1 promotes TRPC6 expression/activation in hypertensive arteries are presently unknown, may include activation of MAP kinases and/or other cellular signaling pathways, and may also directly regulate calcium influx through TRPC channels (4). Further studies are needed to elucidate the regulation of these pathways by IGF-1, especially that in addition to aging, decline of the GH/IGF-1 axis was shown in diabetes, hypophyseal disorders and following traumatic brain injury, all of which have enormous epidemiological importance.Finally, possible species differences have to be considered. The role of TRPC6 in the myogenic response in isolated human cerebral arterioles should also be demonstrated to translate these findings to clinical application to prevent the development of age-related cerebrovascular alterations.GRANTSThis work was supported by National Research, Development and Innovation Office Grant NKFI-FK123798.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSL.T. and P.T. prepared figures; L.T., A.C., N.S., and P.T. drafted manuscript; L.T., A.C., N.S., and P.T. edited and revised manuscript; L.T., A.C., N.S., and P.T. approved final version of manuscript.REFERENCES1. Brayden JE, Earley S, Nelson MT, Reading S. Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow. Clin Exp Pharmacol Physiol 35: 1116–1120, 2008. doi:10.1111/j.1440-1681.2007.04855.x. Crossref | PubMed | ISI | Google Scholar2. Dietrich A, Mederos Y Schnitzler M, Gollasch M, Gross V, Storch U, Dubrovska G, Obst M, Yildirim E, Salanova B, Kalwa H, Essin K, Pinkenburg O, Luft FC, Gudermann T, Birnbaumer L. Increased vascular smooth muscle contractility in TRPC6-/- mice. Mol Cell Biol 25: 6980–6989, 2005. doi:10.1128/MCB.25.16.6980-6989.2005. Crossref | PubMed | ISI | Google Scholar3. Earley S, Waldron BJ, Brayden JE. Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries. Circ Res 95: 922–929, 2004. doi:10.1161/01.RES.0000147311.54833.03. Crossref | PubMed | ISI | Google Scholar4. Kanzaki M, Zhang YQ, Mashima H, Li L, Shibata H, Kojima I. Translocation of a calcium-permeable cation channel induced by insulin-like growth factor-I. Nat Cell Biol 1: 165–170, 1999. doi:10.1038/11086. Crossref | PubMed | ISI | Google Scholar5. Nemeth Z, Hildebrandt E, Ryan MJ, Granger JP, Drummond HA. Pressure-induced constriction of the middle cerebral artery is abolished in TrpC6 knockout mice. Am J Physiol Heart Circ Physiol 319: H42–H50, 2020. doi:10.1152/ajpheart.00126.2020. Link | ISI | Google Scholar6. Toth P, Csiszar A, Tucsek Z, Sosnowska D, Gautam T, Koller A, Schwartzman ML, Sonntag WE, Ungvari Z. Role of 20-HETE, TRPC channels, and BKCa in dysregulation of pressure-induced Ca2+ signaling and myogenic constriction of cerebral arteries in aged hypertensive mice. Am J Physiol Heart Circ Physiol 305: H1698–H1708, 2013. doi:10.1152/ajpheart.00377.2013. Link | ISI | Google Scholar7. Toth P, Tarantini S, Csiszar A, Ungvari Z. Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol 312: H1–H20, 2017. doi:10.1152/ajpheart.00581.2016. Link | ISI | Google Scholar8. Toth P, Tarantini S, Springo Z, Tucsek Z, Gautam T, Giles CB, Wren JD, Koller A, Sonntag WE, Csiszar A, Ungvari Z. Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection. Aging Cell 14: 400–408, 2015. doi:10.1111/acel.12315. Crossref | PubMed | ISI | Google Scholar9. Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S, Deak F, Koller A, Sonntag WE, Csiszar A, Ungvari Z. Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab 33: 1732–1742, 2013. doi:10.1038/jcbfm.2013.143. Crossref | PubMed | ISI | Google Scholar10. Toth P, Tucsek Z, Tarantini S, Sosnowska D, Gautam T, Mitschelen M, Koller A, Sonntag WE, Csiszar A, Ungvari Z. IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice. J Cereb Blood Flow Metab 34: 1887–1897, 2014. doi:10.1038/jcbfm.2014.156. Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESCorrespondence: P. Toth (toth.[email protected]hu). Previous Back to Top Next FiguresReferencesRelatedInformationCited ByVascular calcium signalling and ageing21 November 2021 | The Journal of Physiology, Vol. 599, No. 24Effect of genetic depletion of MMP-9 on neurological manifestations of hypertension-induced intracerebral hemorrhages in aged mice19 August 2021 | GeroScience, Vol. 43, No. 5 More from this issue > Volume 319Issue 1July 2020Pages H159-H161 Copyright & PermissionsCopyright © 2020 the American Physiological Societyhttps://doi.org/10.1152/ajpheart.00403.2020PubMed32559134History Received 29 May 2020 Accepted 13 June 2020 Published online 2 July 2020 Published in print 1 July 2020 Keywordsdegenerinmechanotransductionmyogenic Metrics Downloaded 304 times
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