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

• Published in: Journal of neuroinflammation Vol. 9; no. 1; p. 253
• Main Authors: Silva, Jharon, Polesskaya, Oksana, Knight, Walter, Zheng, Johnny Ting, Granger, Megan, Lopez, Tenée, Ontiveros, Fernando, Feng, Changyong, Yan, Chen, Kasischke, Karl A, Dewhurst, Stephen
• Format: Journal Article
• Language: English
• Published: England BioMed Central 20.11.2012; BioMed Central Ltd; BMC
• Subjects: Animal models; Animals; Arterioles; Arterioles - drug effects; Arterioles - metabolism; Biopterins - analogs & derivatives; Biopterins - pharmacology; Blood Circulation Time; Brain; Carbon Dioxide - pharmacology; Cardiovascular diseases; Cardiovascular System - pathology; Cardiovascular System - virology; Cerebral blood flow; Cerebral Cortex - pathology; Cerebrovascular Circulation - drug effects; Cerebrovascular Circulation - physiology; Cerebrovascular reactivity; Cerebrovascular system; Chlorocebus aethiops; Cognitive ability; COS Cells; Cyclic GMP; Cyclic GMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism; Cyclic nucleotides; Data processing; Disease Models, Animal; Doppler effect; Encephalitis - complications; Encephalitis - etiology; Encephalitis - pathology; Encephalitis - virology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; HIV; HIV Infections - complications; HIV Infections - genetics; HIV-1; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Hypercapnia; Inflammation; Ischemia; Lasers; Lectins - metabolism; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy; Microvasculature; Nitric Oxide - metabolism; Pathology; phosphodiesterase; Phosphodiesterase-5; Proteins; Rodents; Stroke; tat Gene Products, Human Immunodeficiency Virus - genetics; Tat protein; Tat-transgenic mice; tetrahydrobiopterin; Time Factors; Transgenic mice; Vasodilation - drug effects; Vasodilation - physiology
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/1742-2094-9-253

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. 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. 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. 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.