Top

Published in:

Open Access 01-12-2012 | Research

Transient hypercapnia reveals an underlying cerebrovascular pathology in a murine model for HIV-1 associated neuroinflammation: role of NO-cGMP signaling and normalization by inhibition of cyclic nucleotide phosphodiesterase-5

Authors: Jharon Silva, Oksana Polesskaya, Walter Knight, Johnny Ting Zheng, Megan Granger, Tenée Lopez, Fernando Ontiveros, Changyong Feng, Chen Yan, Karl A Kasischke, Stephen Dewhurst

Published in: Journal of Neuroinflammation | Issue 1/2012

Abstract

Background

Cerebral blood flow (CBF) is known to be dysregulated in persons with human immunodeficiency virus 1 (HIV-1), for uncertain reasons. This is an important issue because impaired vasoreactivity has been associated with increased risk of ischemic stroke, elevated overall cardiovascular risk and cognitive impairment.

Methods

To test whether dysregulation of CBF might be due to virally-induced neuroinflammation, we used a well-defined animal model (GFAP-driven, doxycycline-inducible HIV-1 Tat transgenic (Tat-tg) mice). We then exposed the mice to a brief hypercapnic stimulus, and assessed cerebrovascular reactivity by measuring 1) changes in cerebral blood flow, using laser Doppler flowmetry and 2) changes in vascular dilation, using in vivo two-photon imaging.

Results

Exposure to brief hypercapnia revealed an underlying cerebrovascular pathology in Tat-tg mice. In control animals, brief hypercapnia induced a brisk increase in cortical flow (20.8% above baseline) and vascular dilation, as measured by laser Doppler flowmetry and in vivo two-photon microscopy. These responses were significantly attenuated in Tat-tg mice (11.6% above baseline), but cortical microvascular morphology and capillary density were unaltered, suggesting that the functional pathology was not secondary to vascular remodeling. To examine the mechanistic basis for the diminished cerebrovascular response to brief hypercapnia, Tat-tg mice were treated with 1) gisadenafil, a phosphodiesterase 5 (PDE5) inhibitor and 2) tetrahydrobiopterin (BH4). Gisadenafil largely restored the normal increase in cortical flow following hypercapnia in Tat-tg mice (17.5% above baseline), whereas BH4 had little effect. Gisadenafil also restored the dilation of small (<25 μm) arterioles following hypercapnia (19.1% versus 20.6% diameter increase in control and Tat-tg plus gisadenafil, respectively), although it failed to restore full dilation of larger (>25 μm) vessels.

Conclusions

Taken together, these data show that HIV-associated neuroinflammation can cause cerebrovascular pathology through effects on cyclic guanosine monophosphate (cGMP) metabolism and possibly on PDE5 metabolism.

Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE: Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007, 69:1789–1799.CrossRefPubMedPubMedCentral

Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I: CHARTER Group: HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 2010, 75:2087–2096.CrossRefPubMedPubMedCentral

Kraft-Terry SD, Buch SJ, Fox HS, Gendelman HE: A coat of many colors: neuroimmune crosstalk in human immunodeficiency virus infection. Neuron 2009, 64:133–145.CrossRefPubMedPubMedCentral

Letendre SL, Ellis RJ, Ances BM, McCutchan JA: Neurologic complications of HIV disease and their treatment. Top HIV Med 2010, 18:45–55.PubMed

Maini CL, Pigorini F, Pau FM, Volpini V, Galgani S, Rosci MA, Narciso P: Cortical cerebral blood flow in HIV-1-related dementia complex. Nucl Med Commun 1990, 11:639–648.CrossRefPubMed

Tran Dinh YR, Mamo H, Cervoni J, Caulin C, Saimot AC: Disturbances in the cerebral perfusion of human immune deficiency virus-1 seropositive asymptomatic subjects: a quantitative tomography study of 18 cases. J Nucl Med 1990, 31:1601–1607.PubMed

Ajmani A, Habte-Gabr E, Zarr M, Jayabalan V, Dandala S: Cerebral blood flow SPECT with Tc-99 m exametazine correlates in AIDS dementia complex stages. A preliminary report. Clin Nucl Med 1991, 16:656–659.CrossRefPubMed

Woods SW, O'Malley SS, Martini BL, McDougle CJ, Price LH, Krystal JH, Hoffer PB, Kosten TR: SPECT regional cerebral blood flow and neuropsychological testing in non-demented HIV-positive drug abusers: preliminary results. Prog Neuropsychopharmacol Biol Psychiatry 1991, 15:649–662.CrossRefPubMed

Brilla R, Nabavi DG, Schulte-Altedorneburg G, Kemeny V, Reichelt D, Evers S, Schiemann U, Husstedt IW: Cerebral vasculopathy in HIV infection revealed by transcranial Doppler: A pilot study. Stroke 1999, 30:811–813.CrossRefPubMed

10.

Chang L, Ernst T, Leonido-Yee M, Speck O: Perfusion MRI detects rCBF abnormalities in early stages of HIV-cognitive motor complex. Neurology 2000, 54:389–396.CrossRefPubMed

11.

Ances BM, Sisti D, Vaida F, Liang CL, Leontiev O, Perthen JE, Buxton RB, Benson D, Smith DM, Little SJ, Richman DD, Moore DJ, Ellis RJ: HNRC group: Resting cerebral blood flow: a potential biomarker of the effects of HIV in the brain. Neurology 2009, 73:702–708.CrossRefPubMedPubMedCentral

12.

Ances BM, Vaida F, Yeh MJ, Liang CL, Buxton RB, Letendre S, McCutchan JA, Ellis RJ: HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging. J Infect Dis 2010, 201:336–340.CrossRefPubMedPubMedCentral

13.

Ances BM, Vaida F, Cherner M, Yeh MJ, Liang CL, Gardner C, Grant I, Ellis RJ, Buxton RB: HIV and chronic methamphetamine dependence affect cerebral blood flow. J Neuroimmune Pharmacol 2011, 6:409–419.CrossRefPubMed

14.

Bruce-Keller AJ, Turchan-Cholewo J, Smart EJ, Geurin T, Chauhan A, Reid R, Xu R, Nath A, Knapp PE, Hauser KF: Morphine causes rapid increases in glial activation and neuronal injury in the striatum of inducible HIV-1 Tat transgenic mice. Glia 2008, 56:1414–1427.CrossRefPubMedPubMedCentral

15.

Lu SM, Tremblay ME, King IL, Qi J, Reynolds HM, Marker DF, Varrone JJ, Majewska AK, Dewhurst S, Gelbard HA: HIV-1 Tat-induced microgliosis and synaptic damage via interactions between peripheral and central myeloid cells. PLoS One 2011, 6:e23915.CrossRefPubMedPubMedCentral

16.

Andersen MN, Mouritzen C: Effect of acute respiratory and metabolic acidosis on cardiac output and peripheral resistance. Ann Surg 1966, 163:161–168.CrossRefPubMedCentral

17.

Walley KR, Lewis TH, Wood LD: Acute respiratory acidosis decreases left ventricular contractility but increases cardiac output in dogs. Circ Res 1990, 67:628–635.CrossRefPubMed

18.

Ances BM, Greenberg JH, Detre JA: The effects of graded hypercapnia on the activation flow coupling response due to forepaw stimulation in alpha-chloralose anesthetized rats. Brain Res 2001, 911:82–88.CrossRefPubMed

19.

Adachi T, Inanami O, Sato A: Nitric oxide (NO) is involved in increased cerebral cortical blood flow following stimulation of the nucleus basalis of Meynert in anesthetized rats. Neurosci Lett 1992, 139:201–204.CrossRefPubMed

20.

Iadecola C: Does nitric oxide mediate the increases in cerebral blood flow elicited by hypercapnia? Proc Natl Acad Sci USA 1992, 89:3913–3916.CrossRefPubMedPubMedCentral

21.

Wang Q, Paulson OB, Lassen NA: Effect of nitric oxide blockade by NG-nitro-L-arginine on cerebral blood flow response to changes in carbon dioxide tension. J Cereb Blood Flow Metab 1992, 12:947–953.CrossRefPubMed

22.

Parfenova H, Shibata M, Zuckerman S, Mirro R, Leffler CW: Cyclic nucleotides and cerebrovascular tone in newborn pigs. Am J Physiol 1993, 265:H1972-H1982.PubMed

23.

Parfenova H, Shibata M, Zuckerman S, Leffler CW: CO2 and cerebral circulation in newborn pigs: cyclic nucleotides and prostanoids in vascular regulation. Am J Physiol 1994, 266:H1494-H1501.PubMed

24.

Rawson DJ, Ballard S, Barber C, Barker L, Beaumont K, Bunnage M, Cole S, Corless M, Denton S, Ellis D, Floc'h M, Foster L, Gosset J, Holmwood F, Lane C, Leahy D, Mathias J, Maw G, Million W, Poinsard C, Price J, Russel R, Street S, Watson L: The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics. Bioorg Med Chem 2012, 20:498–509.CrossRefPubMed

25.

Watson KJ, Davis J, Jones HM: Application of physiologically based pharmacokinetic modeling to understanding the clinical pharmacokinetics of UK-369,003. Drug Metab Dispos 2011, 39:1203–1213.CrossRefPubMed

26.

Tayeh MA, Marletta MA: Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. Tetrahydrobiopterin is required as a cofactor. J Biol Chem 1989, 264:19654–19658.PubMed

27.

Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H, Tordo P, Pritchard KA Jr: Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 1998, 95:9220–9225.CrossRefPubMedPubMedCentral

28.

Ma M, Nath A: Molecular determinants for cellular uptake of Tat protein of human immunodeficiency virus type 1 in brain cells. J Virol 1997, 71:2495–2499.PubMedPubMedCentral

29.

Mattiacio J, Walter S, Brewer M, Domm W, Friedman AE, Dewhurst S: Dense display of HIV-1 envelope spikes on the lambda phage scaffold does not result in the generation of improved antibody responses to HIV-1 Env. Vaccine 2011, 29:2637–2647.CrossRefPubMedPubMedCentral

30.

Duncan MJ, Bruce-Keller AJ, Conner C, Knapp PE, Xu R, Nath A, Hauser KF: Effects of chronic expression of the HIV-induced protein, transactivator of transcription, on circadian activity rhythms in mice, with or without morphine. Am J Physiol Regul Integr Comp Physiol 2008, 295:R1680-R1687.CrossRefPubMedPubMedCentral

31.

Fitting S, Xu R, Bull C, Buch SK, El-Hage N, Nath A, Knapp PE, Hauser KF: Interactive comorbidity between opioid drug abuse and HIV-1 Tat: chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons. Am J Pathol 2010, 177:1397–1410.CrossRefPubMedPubMedCentral

32.

Polesskaya O, Silva J, Sanfilippo C, Desrosiers T, Sun A, Shen J, Feng C, Polesskiy A, Deane R, Zlokovic B, Deane R, Zlokovic B, Kasischke K, Dewhurst S: Methamphetamine causes sustained depression in cerebral blood flow. Brain Res 2011, 1373:91–100.CrossRefPubMed

33.

Drummond JC, Patel PM: Cerebral Physiology and the Effects of Anesthetics and Techniques. In Miller’s Anesthesia. 5th edition. Edited by Miller RD, Churchill-Livingstone, Orlando, FL; 2000:13.

34.

Marker DF, Tremblay ME, Lu SM, Majewska AK, Gelbard HA: A thin-skull window technique for chronic two-photon in vivo imaging of murine microglia in models of neuroinflammation. J Vis Exp 2010.

35.

Beavo JA, Hardman JG, Sutherland EW: Hydrolysis of cyclic guanosine and adenosine 3',5'-monophosphates by rat and bovine tissues. J Biol Chem 1970, 245:5649–5655.PubMed

36.

Wolff HG: The cerebral circulation. Physiol Rev 1936, 16:545–596.

37.

Yang SP, Krasney JA: Cerebral blood flow and metabolic responses to sustained hypercapnia in awake sheep. J Cereb Blood Flow Metab 1995, 15:115–123.CrossRefPubMed

38.

Wahl M, Schilling L: Regulation of cerebral blood flow-a brief review. Acta Neurochir Suppl (Wien) 1993, 59:3–10.

39.

Theodore S, Cass WA, Nath A, Steiner J, Young K, Maragos WF: Inhibition of tumor necrosis factor-alpha signaling prevents human immunodeficiency virus-1 protein Tat and methamphetamine interaction. Neurobiol Dis 2006, 23:663–668.CrossRefPubMed

40.

Rappaport J, Joseph J, Croul S, Alexander G, Del Valle L, Amini S, Khalili K: Molecular pathway involved in HIV-1-induced CNS pathology: role of viral regulatory protein. Tat. J Leukoc Biol 1999, 65:458–465.PubMed

41.

Philippon V, Vellutini C, Gambarelli D, Harkiss G, Arbuthnott G, Metzger D, Roubin R, Filippi P: The basic domain of the lentiviral Tat protein is responsible for damages in mouse brain: involvement of cytokines. Virology 1994, 205:519–529.CrossRefPubMed

42.

Majno G: Chronic inflammation: links with angiogenesis and wound healing. Am J Pathol 1998, 153:1035–1039.CrossRefPubMedPubMedCentral

43.

Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD: The codependence of angiogenesis and chronic inflammation. FASEB J 1997, 11:457–465.PubMed

44.

Kass DA, Takimoto E, Nagayama T, Champion HC: Phosphodiesterase regulation of nitric oxide signaling. Cardiovasc Res 2007, 75:303–314.CrossRefPubMed

45.

Lacombe P, Oligo C, Domenga V, Tournier-Lasserve E, Joutel A: Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy. Stroke 2005, 36:1053–1058.CrossRefPubMed

46.

Dalkara T, Irikura K, Huang Z, Panahian N, Moskowitz MA: Cerebrovascular responses under controlled and monitored physiological conditions in the anesthetized mouse. J Cereb Blood Flow Metab 1995, 15:631–638.CrossRefPubMed

47.

Detre JA, Ances BM, Takahashi K, Greenberg JH: Signal averaged laser Doppler measurements of activation-flow coupling in the rat forepaw somatosensory cortex. Brain Res 1998, 796:91–98.CrossRefPubMed

48.

Toda N, Ayajiki K, Okamura T: Cerebral blood flow regulation by nitric oxide: recent advances. Pharmacol Rev 2009, 61:62–97.CrossRefPubMed

49.

Faraci FM: Reactive oxygen species: influence on cerebral vascular tone. J Appl Physiol 2006, 100:739–743.CrossRefPubMed

50.

Paladugu R, Fu W, Conklin BS, Lin PH, Lumsden AB, Yao Q, Chen C: Hiv Tat protein causes endothelial dysfunction in porcine coronary arteries. J Vasc Surg 2003, 38:549–556.CrossRefPubMed

51.

de Wit C, Jahrbeck B, Schafer C, Bolz SS, Pohl U: Nitric oxide opposes myogenic pressure responses predominantly in large arterioles in vivo. Hypertension 1998, 31:787–794.CrossRefPubMed

52.

Pohl U, de Wit C: A unique role of NO in the control of blood flow. News Physiol Sci 1999, 14:74–80.PubMed

53.

Glodzik L, Rusinek H, Brys M, Tsui WH, Switalski R, Mosconi L, Mistur R, Pirraglia E, de Santi S, Li Y, Pirraglia E, de Santi S, Li Y, Goldowsky A, de Leon MJ: Framingham cardiovascular risk profile correlates with impaired hippocampal and cortical vasoreactivity to hypercapnia. J Cereb Blood Flow Metab 2011, 31:671–679.CrossRefPubMed

54.

King A, Serena J, Bornstein NM, Markus HS: Does impaired cerebrovascular reactivity predict stroke risk in asymptomatic carotid stenosis? A prospective substudy of the asymptomatic carotid emboli study. Stroke 2011, 42:1550–1555.CrossRef

55.

Silvestrini M, Pasqualetti P, Baruffaldi R, Bartolini M, Handouk Y, Matteis M, Moffa F, Provinciali L, Vernieri F: Cerebrovascular reactivity and cognitive decline in patients with Alzheimer disease. Stroke 2006, 37:1010–1015.CrossRefPubMed

56.

Silvestrini M, Vernieri F, Pasqualetti P, Matteis M, Passarelli F, Troisi E, Caltagirone C: Impaired cerebral vasoreactivity and risk of stroke in patients with asymptomatic carotid artery stenosis. JAMA 2000, 283:2122–2127.CrossRefPubMed

57.

Viticchi G, Falsetti L, Vernieri F, Altamura C, Bartolini M, Luzzi S, Provinciali L, Silvestrini M: Vascular predictors of cognitive decline in patients with mild cognitive impairment. Neurobiol Aging 2012, 33:1–1127.CrossRef

58.

Silvestrini M, Viticchi G, Falsetti L, Balucani C, Vernieri F, Cerqua R, Luzzi S, Bartolini M, Provinciali L: The role of carotid atherosclerosis in Alzheimer's disease progression. J Alzheimers Dis 2011, 25:719–726.PubMed

Title: Transient hypercapnia reveals an underlying cerebrovascular pathology in a murine model for HIV-1 associated neuroinflammation: role of NO-cGMP signaling and normalization by inhibition of cyclic nucleotide phosphodiesterase-5
Authors: Jharon Silva
Oksana Polesskaya
Walter Knight
Johnny Ting Zheng
Megan Granger
Tenée Lopez
Fernando Ontiveros
Changyong Feng
Chen Yan
Karl A Kasischke
Stephen Dewhurst
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-9-253

At a glance: The STEP trials

Springer Medicine

Transient hypercapnia reveals an underlying cerebrovascular pathology in a murine model for HIV-1 associated neuroinflammation: role of NO-cGMP signaling and normalization by inhibition of cyclic nucleotide phosphodiesterase-5

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2012

Differential effects of interleukin-17 receptor signaling on innate and adaptive immunity during central nervous system bacterial infection

Therapeutic targeting of Krüppel-like factor 4 abrogates microglial activation

Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson’s disease

Preserved vascular integrity and enhanced survival following neuropilin-1 inhibition in a mouse model of CD8 T cell-initiated CNS vascular permeability

The immunology of traumatic brain injury: a prime target for Alzheimer’s disease prevention

Podosomes in migrating microglia: components and matrix degradation