title: Defining the role of fluid shear stress in the expression of early signaling markers for calcific aortic valve disease.
abstract: Calcific aortic valve disease (CAVD) is an active process presumably triggered by interplays between cardiovascular risk factors, molecular signaling networks and hemodynamic cues. While earlier studies demonstrated that alterations in fluid shear stress (FSS) on the fibrosa could trigger inflammation, the mechanisms of CAVD pathogenesis secondary to side-specific FSS abnormalities are poorly understood. This knowledge could be critical to the elucidation of key CAVD risk factors such as congenital valve defects, aging and hypertension, which are known to generate FSS disturbances. The objective of this study was to characterize ex vivo the contribution of isolated and combined abnormalities in FSS magnitude and frequency to early valvular pathogenesis. The ventricularis and fibrosa of porcine aortic valve leaflets were exposed simultaneously to different combinations of sub-physiologic/physiologic/supra-physiologic levels of FSS magnitude and frequency for 24, 48 and 72 hours in a double cone-and-plate device. Endothelial activation and paracrine signaling were investigated by measuring cell-adhesion molecule (ICAM-1, VCAM-1) and cytokine (BMP-4, TGF-β1) expressions, respectively. Extracellular matrix (ECM) degradation was characterized by measuring the expression and activity of the proteases MMP-2, MMP-9, cathepsin L and cathepsin S. The effect of the FSS treatment yielding the most significant pathological response was examined over a 72-hour period to characterize the time-dependence of FSS mechano-transduction. While cytokine expression was stimulated under elevated FSS magnitude at normal frequency, ECM degradation was stimulated under both elevated FSS magnitude at normal frequency and physiologic FSS magnitude at abnormal frequency. In contrast, combined FSS magnitude and frequency abnormalities essentially maintained valvular homeostasis. The pathological response under supra-physiologic FSS magnitude peaked at 48 hours but was then maintained until the 72-hour time point. This study confirms the sensitivity of valve leaflets to both FSS magnitude and frequency and suggests the ability of supra-physiologic FSS levels or abnormal FSS frequencies to initiate CAVD mechanisms.
authors.affiliation: Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana, United States of America ; Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Ling
authors.initials: L
authors.lastname: Sun
authors.affiliation: Molecular Biology and Biochemistry, Mayo Clinic School of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Nalini M
authors.initials: NM
authors.lastname: Rajamannan
authors.affiliation: Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana, United States of America ; Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sucosky
mesh_terms: D000704:Analysis of Variance; D001021:Aortic Valve / Q000503:physiopathology; D000082882:Bicuspid Aortic Valve Disease; D001696:Biomechanical Phenomena / Q000502:physiology; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002114:Calcinosis / Q000503:physiopathology*; D056668:Cathepsin L / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006330:Heart Defects, Congenital / Q000503:physiopathology*; D006349:Heart Valve Diseases / Q000503:physiopathology*; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D007136:Immunoglobulins / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D033081:Shear Strength / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D053773:Transforming Growth Factor beta1; D002403:Cathepsins; D056668:Cathepsin L; C028217:cathepsin S; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9