Published online before print April 27, 2006, doi: 10.1161/01.RES.0000224114.65109.4e
© 2006 American Heart Association, Inc.
Integrative Physiology |
Extracellular Matrix Remodeling and Organization in Developing and Diseased Aortic Valves
From the Divisions of Cardiology (R.B.H., D.W.B.), Molecular Cardiovascular Biology (J.L., H.O., K.E.Y.), Pathology (G.H.D.), and Cardiothoracic Surgery (P.B.M.), Cincinnati Children’s Hospital Medical Center, Ohio.
Correspondence to Katherine E. Yutzey, PhD, Associate Professor of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, ML 7020, Cincinnati, OH 45229-3039. Katherine.Yutzey{at}cchmc.org
Heart valve disease is an important cause of morbidity and mortality worldwide. Little is known about valve disease pathogenesis, but increasing evidence implicates a genetic basis for valve disease, suggesting a developmental origin. Although the cellular and molecular processes involved in early valvulogenesis have been well described, less is known about the regulation of valve extracellular matrix (ECM) organization and valvular interstitial cell (VIC) distribution that characterize the mature valve structure. Histochemistry, immunohistochemistry, and electron microscopy were used to examine ECM organization, VIC distribution, and cell proliferation during late valvulogenesis in chicken and mouse. In mature valves, ECM organization is conserved across species, and developmental studies demonstrate that ECM stratification begins during late embryonic cusp remodeling and continues into postnatal life. Cell proliferation decreases concomitant with ECM stratification and VIC compartmentalization. Explanted, stenotic bicuspid aortic valves (BAVs) from pediatric patients were also examined. The diseased valves exhibited disruption of the highly organized ECM and VIC distribution seen in normal valves. Cusps from diseased valves were thickened with increased and disorganized collagens and proteoglycans, decreased and fragmented elastic fibers, and cellular disarray without calcification or cell proliferation. Taken together, these studies show that normal valve development is characterized by spatiotemporal coordination of ECM organization and VIC compartmentalization and that these developmental processes are disrupted in pediatric patients with diseased BAVs.
Key Words: valve disease • extracellular matrix • valvular interstitial cells • cardiac development
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