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Protection against hypoxia‐induced pulmonary hypertension in CX3CR1‐deficient mice correlates with decreased microglia activation
Author(s) -
Oliveira Aline Cristina,
Aquino Victor,
Sharma Ravindra K.,
Lobaton Gilberto,
Harrison Jeffrey K.,
Richards Elaine M.,
Raizada Mohan K.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.625.19
Subject(s) - cx3cr1 , microglia , ventricle , hypoxia (environmental) , medicine , cx3cl1 , inflammation , pulmonary hypertension , green fluorescent protein , endocrinology , chemistry , chemokine , chemokine receptor , biochemistry , organic chemistry , oxygen , gene
Background Microglia are key modulators of the immune response in the brain and can be activated very early in pathology. Our previous studies have indicated that activation of microglial cells and neuro‐inflammation in autonomic brain regions plays a critical role in pulmonary hypertension (PH), possibly by increasing sympathetic activity. Microglial activation is regulated by the chemokine fractalkine, CX3CL1, and its receptor CX3CR1. Lack or deficiency of CX3CR1 was shown to significantly reduce inflammation, and suppress activation and neurotoxicity of microglia/macrophages in experimental ischemic stroke. Aim This study was designed to explore the role of CX3CR1 in microglial activation in PH induced by hypoxia. Methods CX3CR1‐deficient (CX3CR1 GFP/GFP ) mice and Wild‐type (WT) mice (C57BL/6J) were exposed to 3 weeks of hypoxia (H:10%O 2 ) in a ventilated chamber (n=5–8/group). On day 21, animals were anesthetized and a Millar pressure catheter was inserted into the jugular vein and threaded down into the right ventricle to measure right ventricular systolic pressure (RVSP), dP/dt and collect data for spectral analysis, a measure of sympathetic activity. After measuring hemodynamic parameters, blood and tissues were collected and animals were perfused for histological analyses. Results Chronic hypoxia induced PH in WT mice, but not in CX3CR1 GFP/GFP as demonstrated by hemodynamic analysis (shown in the table below) and sympathetic activity (LF/HF: WT‐N: 0.23 ± 0.8; WT‐H:1.19 ± 0.8; CX3CR1 GFP/GFP ‐N: 0.19 ± 0.1; CX3CR1 GFP/GFP ‐H: 0.29 ± 0.05; p<0.001). PH is associated with increase in activated microgial cells in the autonomic brain areas, predominantly in the paraventricular nucleus (PVN). However, exposure of the CX3CR1 GFP/GFP mice to hypoxia did not change microglia activation in the PVN (CX3CR1 GFP/GFP ‐N: 1441 ± 51; CX3CR1 GFP/GFP ‐H: 1541 ± 68). Furthermore, a positive correlation between microglia and RVSP was also observed (R square: 0.4619 p=0.03). Conclusion These data demonstrate a relationship between RVSP and PVN microglia and suggest that microglia activation and neuroinflammation in the autonomic brain areas may be involved in development of PH. Support or Funding Information This research is supported by NIH grant HL102033. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .