Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-beta1-dependent pathway.
OBJECTIVE
Hemodynamics has been associated with aortic valve (AV) inflammation, but the underlying mechanisms are not well understood. Here we tested the hypothesis that altered shear stress conditions stimulate the expression of cytokines and adhesion molecules in AV leaflets via a bone morphogenic protein (BMP)- and transforming growth fact (TGF)-beta1-dependent pathway.


RESULTS
The ventricularis or aortic surface of porcine AV leaflets were exposed for 48 hours to unidirectional pulsatile and bidirectional oscillatory shear stresses ex vivo. Immunohistochemistry was performed to detect expressions of the 4 inflammatory markers VCAM-1, ICAM-1, BMP-4, and TGF-beta1. Exposure of the aortic surface to pulsatile shear stress (altered hemodynamics), but not oscillatory shear stress, increased expression of the inflammatory markers. In contrast, neither pulsatile nor oscillatory shear stress affected expression of the inflammatory markers on the ventricularis surface. The shear stress-dependent expression of VCAM-1, ICAM-1, and BMP-4, but not TGF-beta1, was significantly reduced by the BMP inhibitor noggin, whereas the TGF-beta1 inhibitor SB431542 blocked BMP-4 expression on the aortic surface exposed to pulsatile shear stress.


CONCLUSIONS
The results demonstrate that altered hemodynamics stimulates the expression of AV leaflet endothelial adhesion molecules in a TGF-beta1- and BMP-4-dependent manner, providing some potential directions for future drug-based therapies for AV diseases.
Sucosky
Philippe
P
Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556-5637, USA. Philippe.Sucosky@nd.edu
Balachandran
Kartik
K
Elhammali
Adnan
A
Jo
Hanjoong
H
Yoganathan
Ajit P
AP
D000818:Animals; D001021:Aortic Valve / Q000187:drug effects / Q000276:immunology* / Q000503:physiopathology; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D007249:Inflammation / Q000276:immunology* / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D011673:Pulsatile Flow; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D013552:Swine; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D016207:Cytokines; D018799:Intercellular Adhesion Molecule-1; D053773:Transforming Growth Factor beta1; D019010:Vascular Cell Adhesion Molecule-1; D000099176:Noggin Protein