TY - JOUR
T1 - Endothelial ether lipids link the vasculature to blood pressure, behavior, and neurodegeneration
AU - Spears, Larry D.
AU - Adak, Sangeeta
AU - Dong, Guifang
AU - Wei, Xiaochao
AU - Spyropoulos, George
AU - Zhang, Qiang
AU - Yin, Li
AU - Feng, Chu
AU - Hu, Donghua
AU - Lodhi, Irfan J.
AU - Hsu, Fong Fu
AU - Rajagopal, Rithwick
AU - Noguchi, Kevin K.
AU - Halabi, Carmen M.
AU - Brier, Lindsey
AU - Bice, Annie R.
AU - Lananna, Brian V.
AU - Musiek, Erik S.
AU - Avraham, Oshri
AU - Cavalli, Valeria
AU - Holth, Jerrah K.
AU - Holtzman, David M.
AU - Wozniak, David F.
AU - Culver, Joseph P.
AU - Semenkovich, Clay F.
N1 - Funding Information:
PexRAP het (Dhrs7b+/-) mice were kindly shared by Dr Alexander Moise. This work was supported by the National Institutes of Health grants DK101392, DK20579, DK56341, GM103422, K08HL135400, NS074969, AG061776, NCATS UL1 TR000448, and U54 HD087011; the American Heart Association; the Hope Center for Neurological Disorders; the Knight Alzheimer's Disease Research Center; the Taylor Family Institute for Innovative Psychiatric Research; and the McDonnell Center for Cellular and Molecular Neurobiology. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
G. D. is supported by the China Scholarship Council (CSC) under grant 201608420067.
Publisher Copyright:
© 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
PY - 2021/4
Y1 - 2021/4
N2 - Vascular disease contributes to neurodegeneration, which is associated with decreased blood pressure in older humans. Plasmalogens, ether phospholipids produced by peroxisomes, are decreased in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. However, the mechanistic links between ether phospholipids, blood pressure, and neurodegeneration are not fully understood. Here, we show that endothelium-derived ether phospholipids affect blood pressure, behavior, and neurodegeneration in mice. In young adult mice, inducible endothelial-specific disruption of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, unexpectedly decreased circulating plasmalogens. PexRAP endothelial knockout (PEKO) mice responded normally to hindlimb ischemia but had lower blood pressure and increased plasma renin activity. In PEKO as compared with control mice, tyrosine hydroxylase was decreased in the locus coeruleus, which maintains blood pressure and arousal. PEKO mice moved less, slept more, and had impaired attention to and recall of environmental events as well as mild spatial memory deficits. In PEKO hippocampus, gliosis was increased, and a plasmalogen associated with memory was decreased. Despite lower blood pressure, PEKO mice had generally normal homotopic functional connectivity by optical neuroimaging of the cerebral cortex. Decreased glycogen synthase kinase-3 phosphorylation, a marker of neurodegeneration, was detected in PEKO cerebral cortex. In a co-culture system, PexRAP knockdown in brain endothelial cells decreased glycogen synthase kinase-3 phosphorylation in co-cultured astrocytes that was rescued by incubation with the ether lipid alkylglycerol. Taken together, our findings suggest that endothelium-derived ether lipids mediate several biological processes and may also confer neuroprotection in mice.
AB - Vascular disease contributes to neurodegeneration, which is associated with decreased blood pressure in older humans. Plasmalogens, ether phospholipids produced by peroxisomes, are decreased in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. However, the mechanistic links between ether phospholipids, blood pressure, and neurodegeneration are not fully understood. Here, we show that endothelium-derived ether phospholipids affect blood pressure, behavior, and neurodegeneration in mice. In young adult mice, inducible endothelial-specific disruption of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, unexpectedly decreased circulating plasmalogens. PexRAP endothelial knockout (PEKO) mice responded normally to hindlimb ischemia but had lower blood pressure and increased plasma renin activity. In PEKO as compared with control mice, tyrosine hydroxylase was decreased in the locus coeruleus, which maintains blood pressure and arousal. PEKO mice moved less, slept more, and had impaired attention to and recall of environmental events as well as mild spatial memory deficits. In PEKO hippocampus, gliosis was increased, and a plasmalogen associated with memory was decreased. Despite lower blood pressure, PEKO mice had generally normal homotopic functional connectivity by optical neuroimaging of the cerebral cortex. Decreased glycogen synthase kinase-3 phosphorylation, a marker of neurodegeneration, was detected in PEKO cerebral cortex. In a co-culture system, PexRAP knockdown in brain endothelial cells decreased glycogen synthase kinase-3 phosphorylation in co-cultured astrocytes that was rescued by incubation with the ether lipid alkylglycerol. Taken together, our findings suggest that endothelium-derived ether lipids mediate several biological processes and may also confer neuroprotection in mice.
UR - http://www.scopus.com/inward/record.url?scp=85107745664&partnerID=8YFLogxK
U2 - 10.1016/j.jlr.2021.100079
DO - 10.1016/j.jlr.2021.100079
M3 - Article
C2 - 33847279
AN - SCOPUS:85107745664
SN - 0022-2275
VL - 62
JO - Journal of Lipid Research
JF - Journal of Lipid Research
M1 - 100079
ER -