The Mechanics And Molecular Regulation Of Heart Valve Morphogenesis
Congenital heart defects (CHD) affect over 1% of the American population and are the origin of substantial healthcare costs. A majority of these defects involve malformations of the valvuloseptal apparatus, which is the precursor to the valves of the heart. Due to the necessity of valves for proper heart function, most moderate to severe valve defects require surgical intervention. Corrective surgery is costly and can result in complications and/or restrictions on the patient's lifestyle. Current genetic evidence for CHD is inadequate to explain the variety and prevalence of these defects, suggesting that misguided molecular and mechanical signaling may be responsible. Unfortunately, the role of mechanical and molecular signaling in normal valve development is only beginning to be elucidated, making the detection of defective valves difficult. An understanding of these mechanical and molecular cues and their effect on valve mechanics in normal development is essential for effective treatment of CHDs. In this dissertation, we focus on the capacity of mechanical and molecular signals to direct valve morphology and mechanical properties. We first validate two mechanical testing techniques to characterize the mechanical properties of avian valves through development. This revealed a monotonic increase in valve stiffness which was concomitant with a rapid transition from globular to planar geometry. We then investigated the capacity of transforming growth factor beta 3 (TGF[beta] 3) and serotonin (5-HT) to stimulate biomechanical remodeling in avian valves. TGF[beta] 3 significantly increased valve stiffness through cell contraction, proliferation, and extracellular matrix synthesis. 5-HT modulated TGF[beta] 3 remodeling in both in vitro and in vivo models. This demonstrated a plausible molecular mechanism for the stiffness increase observed during development. To investigate the role of mechanical signaling, we developed a model of growth and remodeling (shape change) that is driven by mechanical stimuli. The consequences of particular assumptions about growth were illustrated with numerical examples. We then built a computational model of valve growth involving both the fluid and solid domains of the atrioventricular (AV) canal and valve. The distribution of the fluid loads on the valve was correlated with the natural morphology of the valve. The computational framework allowed the effects of pressure and shear tractions to be individually interpreted. These results provided a potential mechanical mechanism to explain the valve morphology observed during development. The dissertation concludes with a chapter on teaching and outreach that stemmed from my involvement in the NSF GK-12 program. Conclusions and future directions are discussed.
growth mechanics; atrioventricular cushion; tgfbeta; serotonin
Jenkins, James Thomas
Butcher, Jonathan T.
Vladimirsky, Alexander B.
Theoretical and Applied Mechanics
Ph. D., Theoretical and Applied Mechanics
Doctor of Philosophy
dissertation or thesis