Mechanical modulation of glycosaminoglycan and proteoglycan production by valvular interstitial cells
Grande-Allen, K. Jane
Doctor of Philosophy
Differently loaded regions of the mitral valve contain distinct amounts and proportions of glycosaminoglycans (GAGs) and proteoglycans (PGs); these GAG/PG profiles are altered in abnormal loading conditions such as myxomatous degeneration. However, the role of mechanical stimulation on GAG and PG synthesis by valvular interstitial cells (VICs) is still unclear. This research analyzed first the PGs in differently loaded regions of mitral valve (leaflet and chordae) and then the effects of mechanical strains on GAG and PG synthesis by VICs using an in vitro 3-dimensional tissue-engineering model to develop a deeper understanding of valve mechanobiology. This original research investigated the specific PGs present in human mitral valves and found that the regions in compression (leaflets) are rich in versican and regions in tension (chordae) are rich in decorin and biglycan; these PGs were also detected in the engineered tissues seeded with VICs. Applying constraint increased the synthesis of decorin, biglycan and 4-sulfated GAGs. Constraint also increased versican secretion but reduced its retention within the engineered tissues. The application of constraint was found to be more influential than the directionality (biaxial vs. uniaxial) of strain. Constrained collagen gels containing leaflet cells retained more decorin and biglycan than did those containing chordal cells. The application of cyclic strains decreased the total GAG synthesis, increased the proportions of 4-sulfated GAGs, and reduced the proportions of hyaluronan. Synthesis of the PG versican was increased by leaflet cells and decreased by chordal cells in response to cyclic strain. Chordal cells were found to be more responsive to cyclic strains than leaflet cells, which has implications in the dramatic remodeling of myxomatous chordae tendineae. Synthesis of total GAGs, 4-sulfated GAGs and decorin was found to be strain dependent, whereas synthesis of versican and decorin was frequency dependent. In general, VICs within collagen gels synthesize GAG in proportions and amounts close to that of native valve tissue. This research is the first to show that strains can modulate GAG/PG synthesis by valve cells. These results provide insight into valve mechanobiology and pathology and have implications for understanding the remodeling process of many soft tissues.