Structural alterations of tight junctions are associated with loss of polarity in stroke-prone spontaneously hypertensive rat blood-brain barrier endothelial cells.
The mechanisms leading to stroke in stroke-prone spontaneously hypertensive rats (SHRSP) are not well understood. We tested the hypothesis that the endothelial tight junctions of the blood-brain barrier are altered in SHRSP prior to stroke. We investigated tight junctions in 13-week-old SHRSP, spontaneously hypertensive stroke-resistant rats (SHR) and age-matched Wistar-Kyoto rats (WKY) by electron microscopy and immunocytochemistry. Ultrathin sections showed no difference in junction structure of cerebral capillaries from SHRSP, SHR and WKY, respectively. However, using freeze-fracturing, we observed that the blood-brain barrier specific distribution of tight junction particles between P- and E-face in WKY (58.7+/-3.6%, P-face; 41.2+/-5.59%, E-face) and SHR (53.2+/-19. 3%, P-face; 55.6+/-13.25%, E-face) was changed to an 89.4+/-9.9% predominant E-face association in cerebral capillaries from SHRSP. However, the expression of the tight junction molecules ZO-1, occludin, claudin-1 and claudin-5 was not changed in capillaries of SHRSP. Permeability of brain capillaries from SHRSP was not different compared to SHR and WKY using lanthanum nitrate as a tracer. In contrast, analysis of endothelial cell polarity by distribution of the glucose-1 transporter (Glut-1) revealed that its abluminal:luminal ratio was reduced from 4:1 in SHR and WKY to 1:1 in endothelial cells of cerebral capillaries of SHRSP. In summary, we demonstrate that early changes exist in cerebral capillaries from a genetic model of hypertension-associated stroke. We suggest that a disturbed fence function of the tight junctions in SHRSP blood-brain barrier endothelial cells may lead to subtle changes in polarity. These changes may contribute to the pathogenesis of stroke.
Lippoldt
A
A
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13092 Berlin, Germany. lippoldt@mdc-berlin.de
Kniesel
U
U
Liebner
S
S
Kalbacher
H
H
Kirsch
T
T
Wolburg
H
H
Haller
H
H
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000648:ultrastructure*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000648:ultrastructure*; D051272:Glucose Transporter Type 1; D008565:Membrane Proteins / Q000378:metabolism / Q000648:ultrastructure; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013045:Species Specificity; D019108:Tight Junctions / Q000378:metabolism / Q000648:ultrastructure*
D051272:Glucose Transporter Type 1; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; C495679:Slc2a1 protein, rat