Regulation of Endothelial Activation and Vascular Inflammation by Shear Stress - Bioanalysis Advanced Materials Methods and Devices - page 82

abundant form of NF- B found in vascular endothelial cells. RelA expression is

preferentially found in athero-susceptible regions of the arteries [ 8 ]. The low,
oscillatory shear stress that is exerted in these regions initiate the signalling
pathway that induces the expression of RelA [ 8 ]. Murine studies that involved the
exposure of vascular endothelial cells to low levels of shear stress exhibited an
enhanced activation of the mitogen activated protein kinase JNK1 and a down-
stream transcription factor ATF2 [ 8 ]. Simultaneously, the expression of RelA was
also observed to be increased in the vascular endothelium. However, when JNK1
was genetically abrogated, activation of ATF2 was hindered and RelA expression
was also reduced in the murine vascular endothelium. These observations indicated
that low, oscillatory shear stress influences ATF2 and RelA activity through a
JNK1-dependent mechanism [ 8 ]. The important roles JNK isoforms play in cardio-
vascular injury and disease have been demonstrated previously. This is supported
by animal studies that have revealed that JNK can be activated in arteries in
response to injury, during the development of aneurysms or in atherosclerotic
lesions [ 37 ]. Other studies also report that the gene transfer of a dominant negative
form of JNK1 reduced neointimal formation in injured arteries [ 12 ] and genetic
deletion of JNK2 reduced foam cell formation and EC dysfunction in hypercholes-
terolemia [ 20 ].
Thus, the JNK-ATF2-NK-

k

B signalling pathway might be a key role in promot-
ing inflammation in the vascular endothelium during atherosclerosis influenced by
low, oscillatory shear stress.

k

6.3 Conclusion

Laminar shear stress is vital in maintaining vascular homeostasis and preventing
atherosclerosis. Low, oscillatory shear stress can activate vascular endothelial
cells through different inflammatory mechanisms. This activation can lead to
recruitment of leukocytes that can lead to the development of atherogenic lesions.
By comparing and contrasting the gene expression of various molecules in
regions of laminar shear stress and oscillatory shear stress, the relationship
between blood flow and development of atherogenesis can be understood more
clearly. The conclusion from these studies are that high, laminar shear stress is
atheroprotective and does not activate endothelial cells whereas low, oscillatory
shear stress is pro-atherogenic and can initiate the activation of vascular endothe-
lial cells, thus leading to inflammation seen in the pathogenesis of atherosclerosis.
Therefore, the control of shear stress can be of potential therapeutic interest in the
treatment of atherosclerosis and other diseases where fluctuations of shear stress
can play a role in the pathogenesis.