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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.

Silva J, Polesskaya O, Knight W, Zheng JT, Granger M, Lopez T, Ontiveros F, Feng C, Yan C, Kasischke KA, Dewhurst S - J Neuroinflammation (2012)

Bottom Line: This is an important issue because impaired vasoreactivity has been associated with increased risk of ischemic stroke, elevated overall cardiovascular risk and cognitive impairment.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, NY 14642, USA.

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.

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Dilatory capacity of pial arterioles of Tat-transgenic mice is decreased. (A-F) Representative images of dilatory response of pial arterioles in wild type (WT), Tat-transgenic (Tat-tg), and Tat-tg mice treated with PDE5 inhibitor gisadenafil (PDEi), taken before (A, C, E) and after (B, D, F) exposure to 30 seconds of 6% CO2. 25X magnification. Arrows point to representative arterioles. Scale bar is 50 micrometers (μm). (G) Average magnitude of vessel dilation after exposure to CO2 (all vessels; initial diameters 1 to 50 μm). Data shown were collected from seven WT mice (a total of 23 arterioles were analyzed), seven Tat-tg mice (a total of 36 arterioles), and seven Tat-tg mice treated with PDEi (a total of 45 arterioles). (H) Average magnitude of vessel dilation after exposure to CO2 (small vessels only; initial diameters 1 to 25 μm). These data are a subset of those shown in (G). (I). Average magnitude of vessel dilation after exposure to CO2 (larger vessels only; initial diameters 26 to 50 μm). These data are a subset of the data shown in (G). G-I. Data are plotted as box- plots. Maximum and minimum outliers are represented by whisker endpoints. Box segmentation represents lowest datum within 1.5 interquartile range of lower quartile, median and highest datum within 1.5 interquartile range of the upper quartile. Statistical significance denoted as *P <0.05; **P <0.01; ***P <0.001; or n.s., no significant difference; t-test
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Figure 5: Dilatory capacity of pial arterioles of Tat-transgenic mice is decreased. (A-F) Representative images of dilatory response of pial arterioles in wild type (WT), Tat-transgenic (Tat-tg), and Tat-tg mice treated with PDE5 inhibitor gisadenafil (PDEi), taken before (A, C, E) and after (B, D, F) exposure to 30 seconds of 6% CO2. 25X magnification. Arrows point to representative arterioles. Scale bar is 50 micrometers (μm). (G) Average magnitude of vessel dilation after exposure to CO2 (all vessels; initial diameters 1 to 50 μm). Data shown were collected from seven WT mice (a total of 23 arterioles were analyzed), seven Tat-tg mice (a total of 36 arterioles), and seven Tat-tg mice treated with PDEi (a total of 45 arterioles). (H) Average magnitude of vessel dilation after exposure to CO2 (small vessels only; initial diameters 1 to 25 μm). These data are a subset of those shown in (G). (I). Average magnitude of vessel dilation after exposure to CO2 (larger vessels only; initial diameters 26 to 50 μm). These data are a subset of the data shown in (G). G-I. Data are plotted as box- plots. Maximum and minimum outliers are represented by whisker endpoints. Box segmentation represents lowest datum within 1.5 interquartile range of lower quartile, median and highest datum within 1.5 interquartile range of the upper quartile. Statistical significance denoted as *P <0.05; **P <0.01; ***P <0.001; or n.s., no significant difference; t-test

Mentions: A thinned skull window was prepared over the right somatosensory cortex[34], and Texas Red-dextran was then administered intravenously. Each animal was imaged for 1-minute baseline, then 6% CO2 was then delivered for 30 seconds via nose cone and imaging was continued for a total of 5 minutes. Representative images for the peak responses of WT and Tat-tg mice to intermittent hypercapnia are shown in Figure5. In WT mice, cerebral arterioles, of all sizes dilated as expected in response to brief hypercapnia (Figure5A,B), whereas in Tat-tg mice, this dilatory response was more attenuated (Figure5C,D) in larger vessels (>25 μm). Treatment of Tat-tg mice with gisadenafil largely restored the normal vasodilatory response to hypercapnia (Figure5E,F) by restoring small vessel (<25 μm) dilatory capacity.


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.

Silva J, Polesskaya O, Knight W, Zheng JT, Granger M, Lopez T, Ontiveros F, Feng C, Yan C, Kasischke KA, Dewhurst S - J Neuroinflammation (2012)

Dilatory capacity of pial arterioles of Tat-transgenic mice is decreased. (A-F) Representative images of dilatory response of pial arterioles in wild type (WT), Tat-transgenic (Tat-tg), and Tat-tg mice treated with PDE5 inhibitor gisadenafil (PDEi), taken before (A, C, E) and after (B, D, F) exposure to 30 seconds of 6% CO2. 25X magnification. Arrows point to representative arterioles. Scale bar is 50 micrometers (μm). (G) Average magnitude of vessel dilation after exposure to CO2 (all vessels; initial diameters 1 to 50 μm). Data shown were collected from seven WT mice (a total of 23 arterioles were analyzed), seven Tat-tg mice (a total of 36 arterioles), and seven Tat-tg mice treated with PDEi (a total of 45 arterioles). (H) Average magnitude of vessel dilation after exposure to CO2 (small vessels only; initial diameters 1 to 25 μm). These data are a subset of those shown in (G). (I). Average magnitude of vessel dilation after exposure to CO2 (larger vessels only; initial diameters 26 to 50 μm). These data are a subset of the data shown in (G). G-I. Data are plotted as box- plots. Maximum and minimum outliers are represented by whisker endpoints. Box segmentation represents lowest datum within 1.5 interquartile range of lower quartile, median and highest datum within 1.5 interquartile range of the upper quartile. Statistical significance denoted as *P <0.05; **P <0.01; ***P <0.001; or n.s., no significant difference; t-test
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Figure 5: Dilatory capacity of pial arterioles of Tat-transgenic mice is decreased. (A-F) Representative images of dilatory response of pial arterioles in wild type (WT), Tat-transgenic (Tat-tg), and Tat-tg mice treated with PDE5 inhibitor gisadenafil (PDEi), taken before (A, C, E) and after (B, D, F) exposure to 30 seconds of 6% CO2. 25X magnification. Arrows point to representative arterioles. Scale bar is 50 micrometers (μm). (G) Average magnitude of vessel dilation after exposure to CO2 (all vessels; initial diameters 1 to 50 μm). Data shown were collected from seven WT mice (a total of 23 arterioles were analyzed), seven Tat-tg mice (a total of 36 arterioles), and seven Tat-tg mice treated with PDEi (a total of 45 arterioles). (H) Average magnitude of vessel dilation after exposure to CO2 (small vessels only; initial diameters 1 to 25 μm). These data are a subset of those shown in (G). (I). Average magnitude of vessel dilation after exposure to CO2 (larger vessels only; initial diameters 26 to 50 μm). These data are a subset of the data shown in (G). G-I. Data are plotted as box- plots. Maximum and minimum outliers are represented by whisker endpoints. Box segmentation represents lowest datum within 1.5 interquartile range of lower quartile, median and highest datum within 1.5 interquartile range of the upper quartile. Statistical significance denoted as *P <0.05; **P <0.01; ***P <0.001; or n.s., no significant difference; t-test
Mentions: A thinned skull window was prepared over the right somatosensory cortex[34], and Texas Red-dextran was then administered intravenously. Each animal was imaged for 1-minute baseline, then 6% CO2 was then delivered for 30 seconds via nose cone and imaging was continued for a total of 5 minutes. Representative images for the peak responses of WT and Tat-tg mice to intermittent hypercapnia are shown in Figure5. In WT mice, cerebral arterioles, of all sizes dilated as expected in response to brief hypercapnia (Figure5A,B), whereas in Tat-tg mice, this dilatory response was more attenuated (Figure5C,D) in larger vessels (>25 μm). Treatment of Tat-tg mice with gisadenafil largely restored the normal vasodilatory response to hypercapnia (Figure5E,F) by restoring small vessel (<25 μm) dilatory capacity.

Bottom Line: This is an important issue because impaired vasoreactivity has been associated with increased risk of ischemic stroke, elevated overall cardiovascular risk and cognitive impairment.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, NY 14642, USA.

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.

Show MeSH
Related in: MedlinePlus