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.
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.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, NY 14642, USA.
authors.forename: Jharon
authors.initials: J
authors.lastname: Silva
authors.forename: Oksana
authors.initials: O
authors.lastname: Polesskaya
authors.forename: Walter
authors.initials: W
authors.lastname: Knight
authors.forename: Johnny Ting
authors.initials: JT
authors.lastname: Zheng
authors.forename: Megan
authors.initials: M
authors.lastname: Granger
authors.forename: Tenée
authors.initials: T
authors.lastname: Lopez
authors.forename: Fernando
authors.initials: F
authors.lastname: Ontiveros
authors.forename: Changyong
authors.initials: C
authors.lastname: Feng
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Karl A
authors.initials: KA
authors.lastname: Kasischke
authors.forename: Stephen
authors.initials: S
authors.lastname: Dewhurst
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology; D001776:Blood Circulation Time; D019556:COS Cells; D002245:Carbon Dioxide / Q000494:pharmacology; D002319:Cardiovascular System / Q000473:pathology* / Q000821:virology; D002540:Cerebral Cortex / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D002522:Chlorocebus aethiops; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000150:complications* / Q000209:etiology / Q000473:pathology* / Q000821:virology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D015658:HIV Infections / Q000150:complications / Q000235:genetics; D006801:Humans; D037102:Lectins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D037102:Lectins; D054322:tat Gene Products, Human Immunodeficiency Virus; D002245:Carbon Dioxide; D001708:Biopterins; D009569:Nitric Oxide; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C003402:sapropterin; D006152:Cyclic GMP