Skip to main content

Advertisement

SpringerLink
Log in

Effect of genetic depletion of MMP-9 on neurological manifestations of hypertension-induced intracerebral hemorrhages in aged mice

  • Original Article
  • Published:
GeroScience Aims and scope Submit manuscript

Abstract

Clinical and experimental studies show that hypertension induces intracerebral hemorrhages (ICH), including cerebral microhemorrhages in the aged brain, which contribute to the pathogenesis of vascular cognitive impairment (VCI). Previous studies showed that aging increased oxidative stress-mediated activation of matrix metalloproteinases (MMPs) that importantly contributes to the pathogenesis of ICHs. In particular, oxidative stress has been implicated in activation of MMP-9, which is known to be involved in the degradation of the extracellular matrix and cleavage of collagen IV, a key constituent of the basal membrane of cerebral vessels. To determine the role of MMP-9 activation in the genesis of ICHs, we induced hypertension in 20-month-old MMP-9 null and age-matched control mice by angiotensin II and L-NAME treatment. Contrary to our hypothesis, MMP-9 deficiency did not delay the onset or incidence of neurological consequences of hypertension-induced ICHs. Our results indicate that MMP-9 activation does not play a role in the age-related exacerbation of hypertension-induced ICH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Wafa HA, Wolfe CDA, Emmett E, Roth GA, Johnson CO, Wang Y. Burden of stroke in Europe: thirty-year projections of incidence, prevalence, deaths, and disability-adjusted life years. Stroke. 2020;51:2418–27.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Centers for disease control and prevention. prevalence and most common causes of disability among adults–United States, 2005. MMWR Morb Mortal Wkly Rep. 2009;58:421–6.

    Google Scholar 

  3. Broderick J, Connolly S, Feldmann E, Hanley D, Kase C, Krieger D, Mayberg M, Morgenstern L, Ogilvy CS, Vespa P, Zuccarello M, American Heart Association/American Stroke Association Stroke C, American Heart Association/American Stroke Association High Blood Pressure Research C, Quality of C and Outcomes in Research Interdisciplinary Working G. Guidelines for the management of spontaneous intracerebral hemorrhage in adults 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Circulation. 2007;116:e391-413.

    Article  PubMed  Google Scholar 

  4. Hostettler IC, Seiffge DJ, Werring DJ. Intracerebral hemorrhage: an update on diagnosis and treatment. Expert Rev Neurother. 2019;19:679–94.

    Article  CAS  PubMed  Google Scholar 

  5. Ungvari Z, Tarantini S, Kirkpatrick AC, Csiszar A, Prodan CI. Cerebral microhemorrhages: mechanisms, consequences, and prevention. Am J Physiol Heart Circ Physiol. 2017;312:H1128–43.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Akoudad S, Wolters FJ, Viswanathan A, de Bruijn RF, van der Lugt A, Hofman A, Koudstaal PJ, Ikram MA, Vernooij MW. Association of Cerebral Microbleeds With Cognitive Decline and Dementia. JAMA Neurol. 2016;73:934–43.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Poels MM, Ikram MA, van der Lugt A, Hofman A, Niessen WJ, Krestin GP, Breteler MM, Vernooij MW. Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study. Neurology. 2012;78:326–33.

    Article  CAS  PubMed  Google Scholar 

  8. Hemphill JC 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke. 2001;32:891–7.

    Article  PubMed  Google Scholar 

  9. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9:167–76.

    Article  PubMed  Google Scholar 

  10. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8:355–69.

    Article  PubMed  Google Scholar 

  11. Poels MM, Ikram MA, van der Lugt A, Hofman A, Krestin GP, Breteler MM, Vernooij MW. Incidence of cerebral microbleeds in the general population: the Rotterdam Scan Study. Stroke. 2011;42:656–61.

    Article  PubMed  Google Scholar 

  12. 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. 2015;14:400–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Babici D, Kudej RK, McNulty T, Zhang J, Oydanich M, Berkman T, Nishimura K, Bishop SP, Vatner DE, Vatner SF. Mechanisms of increased vascular stiffness down the aortic tree in aging, premenopausal female monkeys. Am J Physiol Heart Circ Physiol. 2020;319:H222–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. DuPont JJ, Kim SK, Kenney RM, Jaffe IZ. Sex differences in the time course and mechanisms of vascular and cardiac aging in mice: role of the smooth muscle cell mineralocorticoid receptor. Am J Physiol Heart Circ Physiol. 2021;320:H169–80.

    Article  CAS  PubMed  Google Scholar 

  15. Toth L, Czigler A, Szarka N, Toth P. The role of transient receptor potential channels in cerebral myogenic autoregulation in hypertension and aging. Am J Physiol Heart Circ Physiol. 2020;319:H159–61.

    Article  CAS  PubMed  Google Scholar 

  16. Charlton PH, Mariscal Harana J, Vennin S, Li Y, Chowienczyk P, Alastruey J. Modeling arterial pulse waves in healthy aging: a database for in silico evaluation of hemodynamics and pulse wave indexes. Am J Physiol Heart Circ Physiol. 2019;317:H1062–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pagoulatou SZ, Bikia V, Trachet B, Papaioannou TG, Protogerou AD, Stergiopulos N. On the importance of the nonuniform aortic stiffening in the hemodynamics of physiological aging. Am J Physiol Heart Circ Physiol. 2019;317:H1125–33.

    Article  CAS  PubMed  Google Scholar 

  18. Springo Z, Toth P, Tarantini S, Ashpole NM, Tucsek Z, Sonntag WE, Csiszar A, Koller A, Ungvari ZI. Aging impairs myogenic adaptation to pulsatile pressure in mouse cerebral arteries. J Cereb Blood Flow Metab. 2015;35:527–30.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 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. 2013;305:H1698–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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. 2017;312:H1–20.

    Article  PubMed  Google Scholar 

  21. 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. 2013;33:1732–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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. 2014;34:1887–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kim DH, Choi JH, Moon JS, Kim HJ, Cha JK. Association between the severity of cerebral small vessel disease, pulsatility of cerebral arteries, and brachial ankle pulse wave velocity in patients with lacunar infarction. Eur Neurol. 2010;64:247–52.

    Article  PubMed  Google Scholar 

  24. Mackey RH, Sutton-Tyrrell K, Vaitkevicius PV, Sakkinen PA, Lyles MF, Spurgeon HA, Lakatta EG, Kuller LH. Correlates of aortic stiffness in elderly individuals: a subgroup of the Cardiovascular Health Study. Am J Hypertens. 2002;15:16–23.

    Article  PubMed  Google Scholar 

  25. Mitchell GF, van Buchem MA, Sigurdsson S, Gotal JD, Jonsdottir MK, Kjartansson O, Garcia M, Aspelund T, Harris TB, Gudnason V, Launer LJ. Arterial stiffness, pressure and flow pulsatility and brain structure and function: the age, gene/environment susceptibility–Reykjavik study. Brain. 2011;134:3398–407.

    Article  PubMed  PubMed Central  Google Scholar 

  26. O’Sullivan C, Duggan J, Lyons S, Thornton J, Lee M, O’Brien E. Hypertensive target-organ damage in the very elderly. Hypertension. 2003;42:130–5.

    Article  CAS  PubMed  Google Scholar 

  27. Seo WK, Lee JM, Park MH, Park KW, Lee DH. Cerebral microbleeds are independently associated with arterial stiffness in stroke patients. Cerebrovasc Dis. 2008;26:618–23.

    Article  PubMed  Google Scholar 

  28. Shimoyama T, Iguchi Y, Kimura K, Mitsumura H, Sengoku R, Kono Y, Morita M, Mochio S. Stroke patients with cerebral microbleeds on MRI scans have arteriolosclerosis as well as systemic atherosclerosis. Hypertens Res. 2012;35:975–9.

    Article  PubMed  Google Scholar 

  29. Thorin-Trescases N, de Montgolfier O, Pincon A, Raignault A, Caland L, Labbe P, Thorin E. Impact of pulse pressure on cerebrovascular events leading to age-related cognitive decline. Am J Physiol Heart Circ Physiol. 2018;314:H1214–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yabluchanskiy A, Ma Y, Iyer RP, Hall ME, Lindsey ML. Matrix metalloproteinase-9: many shades of function in cardiovascular disease. Physiology (Bethesda). 2013;28:391–403.

    CAS  Google Scholar 

  31. Kaminski AR, Moore ET, Daseke MJ 2nd, Valerio FM, Flynn ER, Lindsey ML. The compendium of matrix metalloproteinase expression in the left ventricle of mice following myocardial infarction. Am J Physiol Heart Circ Physiol. 2020;318:H706–14.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Yabluchanskiy A, Ma Y, Chiao YA, Lopez EF, Voorhees AP, Toba H, Hall ME, Han HC, Lindsey ML, Jin YF. Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction. Am J Physiol Heart Circ Physiol. 2014;306:H1398–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ma Y, Chiao YA, Clark R, Flynn ER, Yabluchanskiy A, Ghasemi O, Zouein F, Lindsey ML, Jin YF. Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence. Cardiovasc Res. 2015;106:421–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang M, Zhang J, Jiang LQ, Spinetti G, Pintus G, Monticone R, Kolodgie FD, Virmani R, Lakatta EG. Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension. 2007;50:219–27.

    Article  CAS  PubMed  Google Scholar 

  35. Wakisaka Y, Chu Y, Miller JD, Rosenberg GA, Heistad DD. Critical role for copper/zinc-superoxide dismutase in preventing spontaneous intracerebral hemorrhage during acute and chronic hypertension in mice. Stroke. 2010;41:790–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee CZ, Xue Z, Zhu Y, Yang GY, Young WL. Matrix metalloproteinase-9 inhibition attenuates vascular endothelial growth factor-induced intracerebral hemorrhage. Stroke. 2007;38:2563–8.

    Article  CAS  PubMed  Google Scholar 

  37. Lee JM, Yin KJ, Hsin I, Chen S, Fryer JD, Holtzman DM, Hsu CY, Xu J. Matrix metalloproteinase-9 and spontaneous hemorrhage in an animal model of cerebral amyloid angiopathy. Ann Neurol. 2003;54:379–82.

    Article  CAS  PubMed  Google Scholar 

  38. Zhao L, Arbel-Ornath M, Wang X, Betensky RA, Greenberg SM, Frosch MP, Bacskai BJ. Matrix metalloproteinase 9-mediated intracerebral hemorrhage induced by cerebral amyloid angiopathy. Neurobiol Aging. 2015;36:2963–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Arantini S, Valcarcel-Ares NM, Yabluchanskiy A, Springo Z, Fulop GA, Ashpole N, Gautam T, Giles CB, Wren JD, Sonntag WE, Csiszar A, Ungvari Z. Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype. Aging Cell. 2017;16:469–79.

    Article  Google Scholar 

  40. Nyul-Toth A, Tarantini S, Kiss T, Toth P, Galvan V, Tarantini A, Yabluchanskiy A, Csiszar A and Ungvari Z. Increases in hypertension-induced cerebral microhemorrhages exacerbate gait dysfunction in a mouse model of Alzheimer's disease. Geroscience. 2020;42(6):1685–98. https://doi.org/10.1007/s11357-020-00256-3

  41. Wakisaka Y, Chu Y, Miller JD, Rosenberg GA, Heistad DD. Spontaneous intracerebral hemorrhage during acute and chronic hypertension in mice. J Cereb Blood Flow Metab. 2010;30:56–69.

    Article  CAS  PubMed  Google Scholar 

  42. Lindsey ML, Escobar GP, Dobrucki LW, Goshorn DK, Bouges S, Mingoia JT, McClister DM Jr, Su H, Gannon J, MacGillivray C, Lee RT, Sinusas AJ, Spinale FG. Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction. Am J Physiol Heart Circ Physiol. 2006;290:H232–9.

    Article  CAS  PubMed  Google Scholar 

  43. Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan D, Shapiro SD, Senior RM, Werb Z. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell. 1998;93:411–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang M, Khazan B, Lakatta EG. Central arterial aging and angiotensin II signaling. Curr Hypertens Rev. 2010;6:266–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Adair JC, Charlie J, Dencoff JE, Kaye JA, Quinn JF, Camicioli RM, Stetler-Stevenson WG, Rosenberg GA. Measurement of gelatinase B (MMP-9) in the cerebrospinal fluid of patients with vascular dementia and Alzheimer disease. Stroke. 2004;35:e159–62.

    Article  CAS  PubMed  Google Scholar 

  46. Moon SK, Cha BY, Lee YC, Nam KS, Runge MS, Patterson C, Kim CH. Age-related changes in matrix metalloproteinase-9 regulation in cultured mouse aortic smooth muscle cells. Exp Gerontol. 2004;39:123–31.

    Article  CAS  PubMed  Google Scholar 

  47. Abilleira S, Montaner J, Molina CA, Monasterio J, Castillo J, Alvarez-Sabin J. Matrix metalloproteinase-9 concentration after spontaneous intracerebral hemorrhage. J Neurosurg. 2003;99:65–70.

    Article  CAS  PubMed  Google Scholar 

  48. Alvarez-Sabin J, Delgado P, Abilleira S, Molina CA, Arenillas J, Ribo M, Santamarina E, Quintana M, Monasterio J, Montaner J. Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke. 2004;35:1316–22.

    Article  CAS  PubMed  Google Scholar 

  49. Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2001;21:1393–400.

    Article  CAS  PubMed  Google Scholar 

  50. Kawakita K, Kawai N, Kuroda Y, Yasashita S, Nagao S. Expression of matrix metalloproteinase-9 in thrombin-induced brain edema formation in rats. J Stroke Cerebrovasc Dis. 2006;15:88–95.

    Article  PubMed  Google Scholar 

  51. Yamani MH, Starling RC, Cook DJ, Tuzcu EM, Abdo A, Paul P, Powell K, Ratliff NB, Yu Y, McCarthy PM, Young JB. Donor spontaneous intracerebral hemorrhage is associated with systemic activation of matrix metalloproteinase-2 and matrix metalloproteinase-9 and subsequent development of coronary vasculopathy in the heart transplant recipient. Circulation. 2003;108:1724–8.

    Article  CAS  PubMed  Google Scholar 

  52. Tang J, Liu J, Zhou C, Alexander JS, Nanda A, Granger DN, Zhang JH. Mmp-9 deficiency enhances collagenase-induced intracerebral hemorrhage and brain injury in mutant mice. J Cereb Blood Flow Metab. 2004;24:1133–45.

    Article  PubMed  Google Scholar 

  53. McNulty M, Spiers P, McGovern E, Feely J. Aging is associated with increased matrix metalloproteinase-2 activity in the human aorta. Am J Hypertens. 2005;18:504–9.

    Article  CAS  PubMed  Google Scholar 

  54. Chung AW, Booth AD, Rose C, Thompson CR, Levin A, van Breemen C. Increased matrix metalloproteinase 2 activity in the human internal mammary artery is associated with ageing, hypertension, diabetes and kidney dysfunction. J Vasc Res. 2008;45:357–62.

    Article  CAS  PubMed  Google Scholar 

  55. Wang M, Takagi G, Asai K, Resuello RG, Natividad FF, Vatner DE, Vatner SF, Lakatta EG. Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension. 2003;41:1308–16.

    Article  CAS  PubMed  Google Scholar 

  56. Li Z, Froehlich J, Galis ZS, Lakatta EG. Increased expression of matrix metalloproteinase-2 in the thickened intima of aged rats. Hypertension. 1999;33:116–23.

    Article  CAS  PubMed  Google Scholar 

  57. Wang M, Lakatta EG. Altered regulation of matrix metalloproteinase-2 in aortic remodeling during aging. Hypertension. 2002;39:865–73.

    Article  CAS  PubMed  Google Scholar 

  58. Spiers JP, Kelso EJ, Siah WF, Edge G, Song G, McDermott BJ, Hennessy M. Alterations in vascular matrix metalloproteinase due to ageing and chronic hypertension: effects of endothelin receptor blockade. J Hypertens. 2005;23:1717–24.

    Article  CAS  PubMed  Google Scholar 

  59. Geng X, Hwang J, Ye J, Shih H, Coulter B, Naudin C, Jun K, Sievers R, Yeghiazarians Y, Lee RJ, Boyle AJ. Aging is protective against pressure overload cardiomyopathy via adaptive extracellular matrix remodeling. Am J Cardiovasc Dis. 2017;7:72–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Liu Y, Zhang M, Hao W, Mihaljevic I, Liu X, Xie K, Walter S, Fassbender K. Matrix metalloproteinase-12 contributes to neuroinflammation in the aged brain. Neurobiol Aging. 2013;34:1231–9.

    Article  PubMed  Google Scholar 

  61. Medley TL, Kingwell BA, Gatzka CD, Pillay P, Cole TJ. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res. 2003;92:1254–61.

    Article  CAS  PubMed  Google Scholar 

  62. Kiss T, Nyul-Toth A, Balasubramanian P, Tarantini S, Ahire C, DelFavero J, Yabluchanskiy A, Csipo T, Farkas E, Wiley G, Garman L, Csiszar A, Ungvari Z. Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain. Geroscience. 2020;42:429–44.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Yu F, Kamada H, Niizuma K, Endo H, Chan PH. Induction of mmp-9 expression and endothelial injury by oxidative stress after spinal cord injury. J Neurotrauma. 2008;25:184–95.

    Article  PubMed  Google Scholar 

  64. Grossetete M, Rosenberg GA. Matrix metalloproteinase inhibition facilitates cell death in intracerebral hemorrhage in mouse. J Cereb Blood Flow Metab. 2008;28:752–63.

    Article  CAS  PubMed  Google Scholar 

  65. Chiao YA, Ramirez TA, Zamilpa R, Okoronkwo SM, Dai Q, Zhang J, Jin YF, Lindsey ML. Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. Cardiovasc Res. 2012;96:444–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, Schoen FJ, Kelly RA, Werb Z, Libby P, Lee RT. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest. 2000;106:55–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ali MM, Mahmoud AM, Le Master E, Levitan I, Phillips SA. Role of matrix metalloproteinases and histone deacetylase in oxidative stress-induced degradation of the endothelial glycocalyx. Am J Physiol Heart Circ Physiol. 2019;316:H647–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ungvari Z, Bailey-Downs L, Gautam T, Sosnowska D, Wang M, Monticone RE, Telljohann R, Pinto JT, de Cabo R, Sonntag WE, Lakatta E, Csiszar A. Age-associated vascular oxidative stress, Nrf2 dysfunction and NF-kB activation in the non-human primate Macaca mulatta. J Gerontol A Biol Sci Med Sci. 2011;66:866–75.

    Article  PubMed  Google Scholar 

  69. Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, Losonczy G, Ballabh P, de Cabo R, Sonntag WE, Csiszar A. Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of Nrf2-mediated antioxidant response. Am J Physiol Heart Circ Physiol. 2011;301:H363-72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Springo Z, Tarantini S, Toth P, Tucsek Z, Koller A, Sonntag WE, Csiszar A, Ungvari Z. Aging exacerbates pressure-induced mitochondrial oxidative stress in mouse cerebral arteries. J Gerontol A Biol Sci Med Sci. 2015;70:1355–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Han BH, Zhou ML, Johnson AW, Singh I, Liao F, Vellimana AK, Nelson JW, Milner E, Cirrito JR, Basak J, Yoo M, Dietrich HH, Holtzman DM, Zipfel GJ. Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice. Proc Natl Acad Sci U S A. 2015;112:E881–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Santisteban MM, Ahn SJ, Lane D, Faraco G, Garcia-Bonilla L, Racchumi G, Poon C, Schaeffer S, Segarra SG, Korbelin J, Anrather J, Iadecola C. Endothelium-macrophage crosstalk mediates blood-brain barrier dysfunction in hypertension. Hypertension. 2020;76:795–807.

    Article  CAS  PubMed  Google Scholar 

  73. Wiesmann M, Roelofs M, van der Lugt R, Heerschap A, Kiliaan AJ and Claassen JA. Angiotensin II, hypertension, and angiotensin II receptor antagonism: roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease. J Cereb Blood Flow Metab. 2017;37(7):2396–413. https://doi.org/10.1177/0271678X16667364

  74. Passos GF, Kilday K, Gillen DL, Cribbs DH, Vasilevko V. Experimental hypertension increases spontaneous intracerebral hemorrhages in a mouse model of cerebral amyloidosis. J Cereb Blood Flow Metab. 2016;36:399–404.

    Article  CAS  PubMed  Google Scholar 

  75. Poulet R, Gentile MT, Vecchione C, Distaso M, Aretini A, Fratta L, Russo G, Echart C, Maffei A, De Simoni MG, Lembo G. Acute hypertension induces oxidative stress in brain tissues. J Cereb Blood Flow Metab. 2006;26:253–62.

    Article  CAS  PubMed  Google Scholar 

  76. Bailey EL, Wardlaw JM, Graham D, Dominiczak AF, Sudlow CL, Smith C. Cerebral small vessel endothelial structural changes predate hypertension in stroke-prone spontaneously hypertensive rats: a blinded, controlled immunohistochemical study of 5- to 21-week-old rats. Neuropathol Appl Neurobiol. 2011;37:711–26.

    Article  CAS  PubMed  Google Scholar 

  77. Mayhan WG, Faraci FM, Heistad DD. Mechanisms of protection of the blood-brain barrier during acute hypertension in chronically hypertensive rats. Hypertension. 1987;9:III101-5.

    Article  CAS  PubMed  Google Scholar 

  78. Barry DI, Strandgaard S, Graham DI, Braendstrup O, Svendsen UG, Vorstrup S, Hemmingsen R, Bolwig TG. Cerebral blood flow in rats with renal and spontaneous hypertension: resetting of the lower limit of autoregulation. J Cereb Blood Flow Metab. 1982;2:347–53.

    Article  CAS  PubMed  Google Scholar 

  79. Mueller SM, Heistad DD. Effect of chronic hypertension on the blood-brain barrier. Hypertension. 1980;2:809–12.

    Article  CAS  PubMed  Google Scholar 

  80. Wakisaka Y, Miller JD, Chu Y, Baumbach GL, Wilson S, Faraci FM, Sigmund CD, Heistad DD. Oxidative stress through activation of NAD(P)H oxidase in hypertensive mice with spontaneous intracranial hemorrhage. J Cereb Blood Flow Metab. 2008;28:1175–85.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by grants from the American Heart Association, the Oklahoma Center for the Advancement of Science and Technology, the National Institute on Aging (R01-AG055395, R01-AG047879; R01-AG038747; R01-AG072295, K01AG073614), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS100782), the National Cancer Institute (NCI;1R01CA255840), the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (U54GM104938, to AY), the Presbyterian Health Foundation, and the NKFIH (Nemzeti Szivlabor). The authors acknowledge the support from the NIA-funded Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), and the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337).

Author information

Author notes

  1. Stefano Tarantini, Andriy Yabluchanskiy, Anna Csiszar, and Zoltan Ungvari contributed equally to this work.

Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma, OK, 73104, USA

    Stefano Tarantini, Andriy Yabluchanskiy, Anna Csiszar & Zoltan Ungvari

  2. Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Stefano Tarantini, Andriy Yabluchanskiy, Anna Csiszar & Zoltan Ungvari

  3. Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Stefano Tarantini, Andriy Yabluchanskiy & Zoltan Ungvari

  4. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary

    Stefano Tarantini & Zoltan Ungvari

  5. Center for Heart and Vascular Research, Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 68102, USA

    Merry L. Lindsey

  6. Research Service, Nebraska-Western Iowa Health Care System, Omaha, NE, 68198, USA

    Merry L. Lindsey

  7. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary

    Anna Csiszar

Authors
  1. Stefano Tarantini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andriy Yabluchanskiy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Merry L. Lindsey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Csiszar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zoltan Ungvari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anna Csiszar.

Ethics declarations

Disclaimer

The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Competing interests

Dr. Anna Csiszar serves as Associate Editor for The Journal of Gerontology, Series A: Biological Sciences and Medical Sciences and GeroScience. Dr. Andriy Yabluchanskiy serves as Guest Editor for The American Journal of Physiology-Heart and Circulatory Physiology. Dr. Zoltan Ungvari serves as Editor-in-Chief for GeroScience and as Consulting Editor for The American Journal of Physiology-Heart and Circulatory Physiology.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tarantini, S., Yabluchanskiy, A., Lindsey, M.L. et al. Effect of genetic depletion of MMP-9 on neurological manifestations of hypertension-induced intracerebral hemorrhages in aged mice. GeroScience 43, 2611–2619 (2021). https://doi.org/10.1007/s11357-021-00402-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-021-00402-5

Keywords

Search

Navigation