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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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Acute exposure to Tat dysregulates cerebrovascular response to hypercapnic challenge. In all panels, cerebral blood flow (CBF) change in response to 30-second exposure to 6% CO2, was measured by bilateral laser Doppler flowmetry (BLDF), in c57Bl mice. (A) CBF change 48 hours after injection with saline into right hemisphere (RH). Intact left hemisphere (LH) serves as a control. Results represent mean values from three mice. (B) Maximum CBF reached in response to 6% CO2, for the data in (A). n.s.: not significant; nonparametric permutation test. (C) CBF change 48 hours after injection with Tat into RH. Intact LH serves as a control. Results represent mean values from four mice. (D) Maximum CBF reached in response to 6% CO2, for the data in (C). **P <0.01, nonparametric permutation test. (E) CBF change 48 hours after injection with heat-inactivated Tat into RH. Intact LH serves as a control. Results represent mean values from four mice. (F) Maximum CBF reached in response to 6% CO2, for the data in (E). (G) CBF change in mice 48 hours after injection with recombinant HIV-1 Env into RH. Intact LH serves as a control. Results represent mean values from four mice. (H) Maximum CBF reached in response to 6% CO2, for the data in (G). (A, C, E, F) Values are expressed as a percentage change from baseline CBF, defined as the mean CBF measured during the one- minute period immediately preceding delivery of CO2. The shadowed area along the X-axis represents the duration of the hypercapnic challenge. All data represent mean ± SEM
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Figure 2: Acute exposure to Tat dysregulates cerebrovascular response to hypercapnic challenge. In all panels, cerebral blood flow (CBF) change in response to 30-second exposure to 6% CO2, was measured by bilateral laser Doppler flowmetry (BLDF), in c57Bl mice. (A) CBF change 48 hours after injection with saline into right hemisphere (RH). Intact left hemisphere (LH) serves as a control. Results represent mean values from three mice. (B) Maximum CBF reached in response to 6% CO2, for the data in (A). n.s.: not significant; nonparametric permutation test. (C) CBF change 48 hours after injection with Tat into RH. Intact LH serves as a control. Results represent mean values from four mice. (D) Maximum CBF reached in response to 6% CO2, for the data in (C). **P <0.01, nonparametric permutation test. (E) CBF change 48 hours after injection with heat-inactivated Tat into RH. Intact LH serves as a control. Results represent mean values from four mice. (F) Maximum CBF reached in response to 6% CO2, for the data in (E). (G) CBF change in mice 48 hours after injection with recombinant HIV-1 Env into RH. Intact LH serves as a control. Results represent mean values from four mice. (H) Maximum CBF reached in response to 6% CO2, for the data in (G). (A, C, E, F) Values are expressed as a percentage change from baseline CBF, defined as the mean CBF measured during the one- minute period immediately preceding delivery of CO2. The shadowed area along the X-axis represents the duration of the hypercapnic challenge. All data represent mean ± SEM

Mentions: To determine whether the vascular response to hypercapnia was altered in an acute model of HIV-induced neuroinflammation[15], c57BL/6 mice age 8to 12 weeks, were anesthetized and administered one of the following by stereotactic intracerebral injection to the cortex of the right hemisphere (RH): 1) 3 μl of saline (0.9% NaCl), 2) 3 μl (1 mg/ml) of recombinant HIV-1 Tat in saline, 3) the same amount of heat-inactivated Tat in saline, or 4) 3 μl (1 mg/ml) of recombinant oligomeric HIV-1 Env in saline (HIV-1YU2 gp140). The cortex of the left hemisphere (LH) was not injected. Two days later, the response to hypercapnia was evaluated using flowmetry with bilaterally placed laser Doppler probes. Each animal served as its own control, by comparing flow on the manipulated right hemisphere (RH) to that on the unmanipulated LH. Figure2A shows data for c57BL/6 mice injected with saline (RH), challenged with 6% CO2 for 30 seconds and recorded over a 5- minute period. This brief exposure to hypercapnia led to a brisk increase in CBF. The peak increase in CBF was not statistically different in the unmanipulated LH (30.6%) and saline-injected RH (21.3%) of these animals (Figure2B) (P = 0.3; nonparametric permutation test). Figure2C shows data for mice injected with Tat (RH) and challenged for 30 seconds with 6% CO2. The magnitude of the induced change in CBF was significantly lower in the Tat-injected RH (7.3%) versus the non-injected LH (26.3%) (P = 0.01; nonparametric permutation test) (Figure2D). Figure2E shows data for control mice injected with heat-inactivated Tat (RH) and challenged for 30 seconds with 6% CO2. The magnitude of the induced change in CBF was similar in the RH (24.6%) and the unmanipulated LH (29.5%) (Figure2F). Finally, Figure2G shows data for mice injected with oligomeric HIV-1 Env (RH) and challenged for 30 seconds with 6% CO2. The magnitude of the induced change in CBF was similar in the RH (29.3%) and the unmanipulated LH (32.1%) (Figure2H).


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)

Acute exposure to Tat dysregulates cerebrovascular response to hypercapnic challenge. In all panels, cerebral blood flow (CBF) change in response to 30-second exposure to 6% CO2, was measured by bilateral laser Doppler flowmetry (BLDF), in c57Bl mice. (A) CBF change 48 hours after injection with saline into right hemisphere (RH). Intact left hemisphere (LH) serves as a control. Results represent mean values from three mice. (B) Maximum CBF reached in response to 6% CO2, for the data in (A). n.s.: not significant; nonparametric permutation test. (C) CBF change 48 hours after injection with Tat into RH. Intact LH serves as a control. Results represent mean values from four mice. (D) Maximum CBF reached in response to 6% CO2, for the data in (C). **P <0.01, nonparametric permutation test. (E) CBF change 48 hours after injection with heat-inactivated Tat into RH. Intact LH serves as a control. Results represent mean values from four mice. (F) Maximum CBF reached in response to 6% CO2, for the data in (E). (G) CBF change in mice 48 hours after injection with recombinant HIV-1 Env into RH. Intact LH serves as a control. Results represent mean values from four mice. (H) Maximum CBF reached in response to 6% CO2, for the data in (G). (A, C, E, F) Values are expressed as a percentage change from baseline CBF, defined as the mean CBF measured during the one- minute period immediately preceding delivery of CO2. The shadowed area along the X-axis represents the duration of the hypercapnic challenge. All data represent mean ± SEM
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: Acute exposure to Tat dysregulates cerebrovascular response to hypercapnic challenge. In all panels, cerebral blood flow (CBF) change in response to 30-second exposure to 6% CO2, was measured by bilateral laser Doppler flowmetry (BLDF), in c57Bl mice. (A) CBF change 48 hours after injection with saline into right hemisphere (RH). Intact left hemisphere (LH) serves as a control. Results represent mean values from three mice. (B) Maximum CBF reached in response to 6% CO2, for the data in (A). n.s.: not significant; nonparametric permutation test. (C) CBF change 48 hours after injection with Tat into RH. Intact LH serves as a control. Results represent mean values from four mice. (D) Maximum CBF reached in response to 6% CO2, for the data in (C). **P <0.01, nonparametric permutation test. (E) CBF change 48 hours after injection with heat-inactivated Tat into RH. Intact LH serves as a control. Results represent mean values from four mice. (F) Maximum CBF reached in response to 6% CO2, for the data in (E). (G) CBF change in mice 48 hours after injection with recombinant HIV-1 Env into RH. Intact LH serves as a control. Results represent mean values from four mice. (H) Maximum CBF reached in response to 6% CO2, for the data in (G). (A, C, E, F) Values are expressed as a percentage change from baseline CBF, defined as the mean CBF measured during the one- minute period immediately preceding delivery of CO2. The shadowed area along the X-axis represents the duration of the hypercapnic challenge. All data represent mean ± SEM
Mentions: To determine whether the vascular response to hypercapnia was altered in an acute model of HIV-induced neuroinflammation[15], c57BL/6 mice age 8to 12 weeks, were anesthetized and administered one of the following by stereotactic intracerebral injection to the cortex of the right hemisphere (RH): 1) 3 μl of saline (0.9% NaCl), 2) 3 μl (1 mg/ml) of recombinant HIV-1 Tat in saline, 3) the same amount of heat-inactivated Tat in saline, or 4) 3 μl (1 mg/ml) of recombinant oligomeric HIV-1 Env in saline (HIV-1YU2 gp140). The cortex of the left hemisphere (LH) was not injected. Two days later, the response to hypercapnia was evaluated using flowmetry with bilaterally placed laser Doppler probes. Each animal served as its own control, by comparing flow on the manipulated right hemisphere (RH) to that on the unmanipulated LH. Figure2A shows data for c57BL/6 mice injected with saline (RH), challenged with 6% CO2 for 30 seconds and recorded over a 5- minute period. This brief exposure to hypercapnia led to a brisk increase in CBF. The peak increase in CBF was not statistically different in the unmanipulated LH (30.6%) and saline-injected RH (21.3%) of these animals (Figure2B) (P = 0.3; nonparametric permutation test). Figure2C shows data for mice injected with Tat (RH) and challenged for 30 seconds with 6% CO2. The magnitude of the induced change in CBF was significantly lower in the Tat-injected RH (7.3%) versus the non-injected LH (26.3%) (P = 0.01; nonparametric permutation test) (Figure2D). Figure2E shows data for control mice injected with heat-inactivated Tat (RH) and challenged for 30 seconds with 6% CO2. The magnitude of the induced change in CBF was similar in the RH (24.6%) and the unmanipulated LH (29.5%) (Figure2F). Finally, Figure2G shows data for mice injected with oligomeric HIV-1 Env (RH) and challenged for 30 seconds with 6% CO2. The magnitude of the induced change in CBF was similar in the RH (29.3%) and the unmanipulated LH (32.1%) (Figure2H).

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