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

BackgroundCerebral 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.MethodsTo 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.ResultsExposure 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.ConclusionsTaken 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.

Chronic Central Nervous System Expression of HIV‐1 Tat Leads to Accelerated Rarefaction of Neocortical Capillaries and Loss of Red Blood Cell Velocity Heterogeneity

“…Investigation of literature on rarefactive events in the peripheral microvasculature suggests a prominent role for NOS dysregulation—including chronic inhibition of NOS or loss of endothelial NOS . Our group recently demonstrated that acute intracranial exposure (3 weeks) to Tat produced a dilatory dysfunction in the pial arterioles in Tat‐tg animals, as a consequence of changes in the Nitric Oxide/Cyclic GMP (NO‐cGMP) signaling axis .…”

“…While the mechanism(s) leading to NCI are incompletely understood, it has been correlated with increased monocyte activation within the CNS, suggesting that neuroinflammation may contribute significantly to HAND . Neuroinflammation has also been linked to neuronal injury in animal models for HIV infection —but additional mechanisms likely contribute to the pathogenesis of HAND, including cerebrovascular dysfunction .…”

“…In addition, there has been a reported increase in both hemorrhagic and ischemic stroke in HIV‐infected people , as well as frequent vascular complications that may contribute to HAND . We recently showed that acute, intracranial exposure of mice to HIV‐1 Tat resulted in decreased CVR in response to hypercapnic challenge . Importantly, attenuation of CVR has been associated with increased risk of ischemic stroke, elevated overall cardiovascular risk, and cognitive impairment .…”

Quantification of Cerebral Vascular Architecture using Two-photon Microscopy in a Mouse Model of HIV-induced Neuroinflammation

“…The in vivo imaging technique allows for the study of other parameters including, but not limited to, red blood cell velocity, arteriole dilation, and red blood cell flux 7,12 , which may also be able to be examined in longitudinal studies. Furthermore, it can easily be adapted and modified to study research questions related to brain microvascular structure.…”

Notch signaling in cerebrovascular diseases (Review)

“…A variety of inflammatory cytokines take part in the neuroinflammation. Evidence indicates that acute neuroinflammation is benefcial to damage repair in the nervous system, whereas chronic neuroinflammation aggravates the pathological events occurring in the brain ( 56 – 59 ). In addition, neuroinflammation has been demonstrated to be crucial for the pathogenesis of cerebrovascular diseases ( 56 ).…”