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Diabetes-related sex differences in the brain endothelin system following
ischemia in vivo and in human brain endothelial cells in vitro.
Abdul Y, Li W, Vargas JD, Grant E, He L, Jamil S, Ergul A
Submitted Externally on 9/28/2020
Canadian journal of physiology and pharmacology
Volume : Pages
98 : 587 - 595
The endothelin (ET) system has been implicated to contribute to the
pathophysiology of cognitive impairment and stroke in experimental diabetes. Our
goals were to test the hypotheses that (1) circulating and (or) periinfarct ET-1
levels are elevated after stroke in both sexes and this increase is greater in
diabetes, (2) ET receptors are differentially regulated in the diabetic brain,
(3) brain microvascular endothelial cells (BMVEC) of female and male origin
express the ETA receptor subtype, and (4) diabetes- and stroke-mimicking
conditions increase ET-1 levels in BMVECs of both sexes. Control and diabetic
rats were randomized to sham or stroke surgery. BMVECs of male (hBEC5i) and
female (hCMEC/D3) origin, cultured under normal and diabetes-mimicking
conditions, were exposed to normoxia or hypoxia. Circulating ET-1 levels were
higher in diabetic animals and this was more pronounced in the male cohort.
Stroke did not further increase plasma ET-1. Tissue ET-1 levels were increased
after stroke only in males, whereas periinfarct ET-1 increased in both control
and diabetic females. Male BMVECs secreted more ET-1 than female cells and
hypoxia increased ET-1 levels in both cell types. There was sexually dimorphic
regulation of ET receptors in both tissue and cell culture samples. There are
sex differences in the stroke- and diabetes-mediated changes in the brain ET
system at the endothelial and tissue levels.
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