TY - JOUR
T1 - Maladaptive matrix remodeling and regional biomechanical dysfunction in a mouse model of aortic valve disease
AU - Krishnamurthy, Varun K.
AU - Opoka, Amy M.
AU - Kern, Christine B.
AU - Guilak, Farshid
AU - Narmoneva, Daria A.
AU - Hinton, Robert B.
N1 - Funding Information:
We thank Dr. Santanu Chakraborty, Dr. Kathryn Rafferty, Abdul Sheikh, Jennifer Hurley and Bob Nielsen for their assistance. We also thank Dr. Dean Y. Li (University of Utah) for providing the elastin knockout mice, and Dr. Robert P. Mecham (Washington University) for helpful discussions. This study was supported by the AHA 09PRE2230162 (VKK), Cincinnati ESU Research Travel Grant (VKK), and the National Institutes of Health AR15768 (FG), DK078814 (DAN), and HL085122 (RBH). There are no conflicts of interests.
PY - 2012/4
Y1 - 2012/4
N2 - Aortic valve disease (AVD) occurs in 2.5% of the general population and often requires surgical intervention. Aortic valve malformation (AVM) underlies the majority of cases, suggesting a developmental etiology. Elastin haploinsufficiency results in complex cardiovascular problems, and 20-45% of patients have AVM and/or AVD. Elastin insufficient (Eln+/-) mice demonstrate AVM and latent AVD due to abnormalities in the valve annulus region. The objective of this study was to examine extracellular matrix (ECM) remodeling and biomechanical properties in regional aortic valve tissue and determine the impact of early AVM on late AVD in the Eln+/- mouse model. Aortic valve ECM composition and remodeling from juvenile, adult, and aged stages were evaluated in Eln+/- mice using histology, ELISA, immunohistochemistry and gelatin zymography. Aortic valve tissue biomechanical properties were determined using micropipette aspiration. Cartilage-like nodules were demonstrated within the valve annulus region at all stages identifying a developmental abnormality preceding AVD. Interestingly, maladaptive ECM remodeling was observed in early AVM without AVD and worsened with late AVD, as evidenced by increased MMP-2 and MMP-9 expression and activity, as well as abnormalities in ADAMTS-mediated versican processing. Cleaved versican was increased in the valve annulus region of aged Eln+/- mice, and this abnormality correlated temporally with adverse alterations in valve tissue biomechanical properties and the manifestation of AVD. These findings identify maladaptive ECM remodeling in functional AVM as an early disease process with a progressive natural history, similar to that seen in human AVD, emphasizing the importance of the annulus region in pathogenesis. Combining molecular and engineering approaches provides complementary mechanistic insights that may be informative in the search for new therapeutic targets and durable valve bioprostheses.
AB - Aortic valve disease (AVD) occurs in 2.5% of the general population and often requires surgical intervention. Aortic valve malformation (AVM) underlies the majority of cases, suggesting a developmental etiology. Elastin haploinsufficiency results in complex cardiovascular problems, and 20-45% of patients have AVM and/or AVD. Elastin insufficient (Eln+/-) mice demonstrate AVM and latent AVD due to abnormalities in the valve annulus region. The objective of this study was to examine extracellular matrix (ECM) remodeling and biomechanical properties in regional aortic valve tissue and determine the impact of early AVM on late AVD in the Eln+/- mouse model. Aortic valve ECM composition and remodeling from juvenile, adult, and aged stages were evaluated in Eln+/- mice using histology, ELISA, immunohistochemistry and gelatin zymography. Aortic valve tissue biomechanical properties were determined using micropipette aspiration. Cartilage-like nodules were demonstrated within the valve annulus region at all stages identifying a developmental abnormality preceding AVD. Interestingly, maladaptive ECM remodeling was observed in early AVM without AVD and worsened with late AVD, as evidenced by increased MMP-2 and MMP-9 expression and activity, as well as abnormalities in ADAMTS-mediated versican processing. Cleaved versican was increased in the valve annulus region of aged Eln+/- mice, and this abnormality correlated temporally with adverse alterations in valve tissue biomechanical properties and the manifestation of AVD. These findings identify maladaptive ECM remodeling in functional AVM as an early disease process with a progressive natural history, similar to that seen in human AVD, emphasizing the importance of the annulus region in pathogenesis. Combining molecular and engineering approaches provides complementary mechanistic insights that may be informative in the search for new therapeutic targets and durable valve bioprostheses.
KW - Aortic valve annulus
KW - Biomedical engineering
KW - Elastin haploinsufficiency
KW - Micropipette aspiration
KW - Valve development
UR - http://www.scopus.com/inward/record.url?scp=84857783542&partnerID=8YFLogxK
U2 - 10.1016/j.matbio.2012.01.001
DO - 10.1016/j.matbio.2012.01.001
M3 - Article
C2 - 22265892
AN - SCOPUS:84857783542
SN - 0945-053X
VL - 31
SP - 197
EP - 205
JO - Matrix Biology
JF - Matrix Biology
IS - 3
ER -