Date of Award
Doctor of Philosophy (PhD)
Hemodynamic forces drive cardiovascular morphogenesis and remodeling in the developing embryo. Changes to the embryonic hemodynamic environment have been shown to induce a variety of congenital heart defects, but little attention has been given to vasculature-specific defects. Although vascular development has been widely studied in the context of genetics and molecular biology, this work investigates the impact of hemodynamic forces on arterial development and mechanics.
The dorsal aorta (DA) is the first intraembryonic vessel to form. Its passive mechanical properties are determined by the deposition of extracellular matrix (ECM) proteins, a hallmark of arterial maturation. We hypothesized that hemodynamic changes affect the structure,
composition, and mechanical behavior of the DA. Throughout this thesis, we quantitatively described the developing ECM and resulting mechanical response of DAs in both normal and hemodynamically-challenged conditions. We used a combination of experimental and
computational approaches to explore the biophysical mechanisms linking blood flow and DA maturation.
In the chick embryo, arterial maturation begins at Hamburger-Hamilton (HH) stage 28 (approximately 6 days of incubation). We used vitelline vein ligation (VVL) to acutely reduce flow in HH18 chick embryos, but additionally discovered a later drop in flow at HH36. In the interim, we found that this triggered the downregulation of several shear-responsive genes known to impact ECM production and degradation. Subsequent examination of ECM protein content revealed that elastin was reduced and collagen was increased. Elastic fiber related genes were upregulated to compensate for these shear-induced ECM changes. Together,
these effects are likely to result in arterial stiffening and increased vascular resistance, thus accounting for further hemodynamic perturbations. Our work shows that the DA's response to reduced flow invokes coupled mechanisms for shear regulation and matrix deposition with potentially long-term effects on vascular development.
Although models of adult arterial mechanics have been developed over the years, there have been very few attempts to model arteries over the course of embryonic development. We determined constituent-specific constitutive relationships and their respective elastic and
viscoelastic properties through uniaxial tensile testing protocols. We accurately predicted experimentally observed increases in DA stiffening and energy loss using elastic and quasilinear viscoelastic models. Having characterized mechanical properties and ECM transmural distributions for the embryonic DA, we found that these differed substantially from adult elastic arteries. Accounting for these differences, we developed a model of growth and remodeling to successfully predict increased residual strains in DAs from VVL embryos. Our computational methods are the first to incorporate experimentally determined material properties for embryonic arteries.
The work described in this thesis enables further study of the role of hemodynamics on arterial mechanics during early embryonic development. Our current findings establish a strong link between flow and the embryonic artery's ECM and mechanical characteristics.
Further studies may elucidate how these mechanical forces result in vascular developmental defects.
Larry Jessica A. Taber Wagenseil
Robert Mecham, Ruth Okamoto, Lori Setton,