Laminar shear stress regulates endothelial kinin B1 receptor expression and function: potential implication in atherogenesis.
OBJECTIVE
The proinflammatory phenotype induced by low laminar shear stress (LSS) is implicated in atherogenesis. The kinin B1 receptor (B1R), known to be induced by inflammatory stimuli, exerts many proinflammatory effects including vasodilatation and leukocyte recruitment. We investigated whether low LSS is a stimulus for endothelial B1R expression and function.


RESULTS
Human and mouse atherosclerotic plaques expressed high level of B1R mRNA and protein. In addition, B1R expression was upregulated in the aortic arch (low LSS region) of ApoE(-/-) mice fed a high-fat diet compared to vascular regions of high LSS and animals fed normal chow. Of interest, a greater expression of B1R was noticed in endothelial cells from regions of low LSS in aortic arch of ApoE(-/-) mice. B1R was also upregulated in human umbilical vein endothelial cells (HUVECs) exposed to low LSS (0 to 2 dyn/cm(2)) compared to physiological LSS (6 to 10 dyn/cm(2)): an effect similarly evident in murine vascular tissue perfused ex vivo. Functionally, B1R activation increased prostaglandin and CXCL5 expression in cells exposed to low, but not physiological, LSS. IL-1beta and ox-LDL induced B1R expression and function in HUVECs, a response substantially enhanced under low LSS conditions and inhibited by blockade of NFkappaB activation.


CONCLUSIONS
Herein, we show that LSS is a major determinant of functional B1R expression in endothelium. Furthermore, whereas physiological high LSS is a powerful repressor of this inflammatory receptor, low LSS occurring [corrected] at sites of atheroma is associated with substantial upregulation, identifying this receptor as a potential therapeutic target.
Duchene
Johan
J
William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, London, UK.
Cayla
Cécile
C
Vessillier
Sandrine
S
Scotland
Ramona
R
Yamashiro
Kazuo
K
Lecomte
Florence
F
Syed
Irfan
I
Vo
Phuong
P
Marrelli
Alessandra
A
Pitzalis
Costantino
C
Cipollone
Francesco
F
Schanstra
Joost
J
Bascands
Jean-Loup
JL
Hobbs
Adrian J
AJ
Perretti
Mauro
M
Ahluwalia
Amrita
A
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism*; D001665:Binding Sites; D015153:Blotting, Western; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033081:Shear Strength / Q000502:physiology; D015398:Signal Transduction; D013314:Stress, Mechanical; D013312:Stress, Physiological / Q000502:physiology*; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
D001057:Apolipoproteins E; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1