PMID- 34465229
OWN - NLM
STAT- MEDLINE
DCOM- 20220208
LR  - 20231016
IS  - 1559-7016 (Electronic)
IS  - 0271-678X (Print)
IS  - 0271-678X (Linking)
VI  - 42
IP  - 1
DP  - 2022 Jan
TI  - Amyloid-beta disrupts unitary calcium entry through endothelial NMDA receptors in 
      mouse cerebral arteries.
PG  - 145-161
LID - 10.1177/0271678X211039592 [doi]
AB  - Transient increases in intracellular Ca(2+) activate endothelium-dependent 
      vasodilatory pathways. This process is impaired in cerebral amyloid angiopathy, 
      where amyloid-beta((1-40)) accumulates around blood vessels. In neurons, amyloid-beta 
      impairs the Ca(2+)-permeable N-methyl-D-aspartate receptor (NMDAR), a mediator of 
      endothelium-dependent dilation in arteries. We hypothesized that 
      amyloid-beta((1-40)) reduces NMDAR-elicited Ca(2+) signals in mouse cerebral artery 
      endothelial cells, blunting dilation. Cerebral arteries isolated from 
      4-5 months-old, male and female cdh5:Gcamp8 mice were used for imaging of unitary 
      Ca(2+) influx through NMDAR (NMDAR sparklets) and intracellular Ca(2+) 
      transients. The NMDAR agonist NMDA (10 micromol/L) increased frequency of NMDAR 
      sparklets and intracellular Ca(2+) transients in endothelial cells; these effects 
      were prevented by NMDAR antagonists D-AP5 and MK-801. Next, we tested if 
      amyloid-beta((1-40)) impairs NMDAR-elicited Ca(2+) transients. Cerebral arteries 
      incubated with amyloid-beta((1-40)) (5 micromol/L) exhibited reduced NMDAR sparklets and 
      intracellular Ca(2+) transients. Lastly, we observed that NMDA-induced dilation 
      of pial arteries is reduced by acute intraluminal amyloid-beta((1-40)), as well as 
      in a mouse model of Alzheimer's disease, the 5x-FAD, linked to downregulation of 
      Grin1 mRNA compared to wild-type littermates. These data suggest that endothelial 
      NMDAR mediate dilation via Ca(2+)-dependent pathways, a process disrupted by 
      amyloid-beta((1-40)) and impaired in 5x-FAD mice.
FAU - Peters, Emily C
AU  - Peters EC
AUID- ORCID: 0000-0001-7672-3510
AD  - Department of Physiology, University of Arizona College of Medicine Tucson, 
      Tucson, AZ, USA.
FAU - Gee, Michael T
AU  - Gee MT
AD  - Department of Physiology, University of Arizona College of Medicine Tucson, 
      Tucson, AZ, USA.
FAU - Pawlowski, Lukas N
AU  - Pawlowski LN
AD  - Department of Physiology, University of Arizona College of Medicine Tucson, 
      Tucson, AZ, USA.
FAU - Kath, Allison M
AU  - Kath AM
AD  - Department of Physiology, University of Arizona College of Medicine Tucson, 
      Tucson, AZ, USA.
FAU - Polk, Felipe D
AU  - Polk FD
AUID- ORCID: 0000-0001-7890-4737
AD  - Department of Physiology, University of Arizona College of Medicine Tucson, 
      Tucson, AZ, USA.
FAU - Vance, Christopher J
AU  - Vance CJ
AD  - Department of Physiology, University of Arizona College of Medicine Tucson, 
      Tucson, AZ, USA.
FAU - Sacoman, Juliana L
AU  - Sacoman JL
AD  - Department of Physiology, University of Arizona College of Medicine Tucson, 
      Tucson, AZ, USA.
FAU - Pires, Paulo W
AU  - Pires PW
AUID- ORCID: 0000-0001-5972-4554
AD  - Department of Physiology, University of Arizona College of Medicine Tucson, 
      Tucson, AZ, USA.
AD  - Sarver Heart Center, University of Arizona College of Medicine Tucson, Tucson, 
      AZ, USA.
LA  - eng
GR  - R00 HL140106/HL/NHLBI NIH HHS/United States
GR  - R24 HL120847/HL/NHLBI NIH HHS/United States
GR  - T32 GM139779/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210831
PL  - United States
TA  - J Cereb Blood Flow Metab
JT  - Journal of cerebral blood flow and metabolism : official journal of the 
      International Society of Cerebral Blood Flow and Metabolism
JID - 8112566
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Peptide Fragments)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (amyloid beta-protein (1-40))
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Alzheimer Disease/genetics/*metabolism
MH  - Amyloid beta-Peptides/genetics/*metabolism
MH  - Animals
MH  - Calcium/*metabolism
MH  - *Calcium Signaling
MH  - Cerebral Arteries/*metabolism
MH  - Disease Models, Animal
MH  - Endothelium, Vascular/*metabolism
MH  - Female
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Peptide Fragments/genetics/*metabolism
MH  - Receptors, N-Methyl-D-Aspartate/genetics/*metabolism
PMC - PMC8721780
OTO - NOTNLM
OT  - N-methyl-D-aspartate receptor
OT  - amyloid-beta
OT  - cerebral amyloid angiopathy
OT  - endothelium Ca2+ signaling
OT  - endothelium-dependent dilation
COIS- Declaration of conflicting interests: The author(s) declared no potential 
      conflicts of interest with respect to the research, authorship, and/or 
      publication of this article.
EDAT- 2021/09/02 06:00
MHDA- 2022/02/09 06:00
PMCR- 2022/08/31
CRDT- 2021/09/01 05:40
PHST- 2021/09/02 06:00 [pubmed]
PHST- 2022/02/09 06:00 [medline]
PHST- 2021/09/01 05:40 [entrez]
PHST- 2022/08/31 00:00 [pmc-release]
AID - 10.1177_0271678X211039592 [pii]
AID - 10.1177/0271678X211039592 [doi]
PST - ppublish
SO  - J Cereb Blood Flow Metab. 2022 Jan;42(1):145-161. doi: 10.1177/0271678X211039592. 
      Epub 2021 Aug 31.