Mechanical Factors in Maturation of the Large Artery Wall

Washington University, Saint Louis MO

Investigators

Abstract

The large arteries are composed of smooth muscle cells surrounded by an extracellular matrix that provides reversible elasticity. The arterial wall distends when blood is pumped out as the heart contracts, and then returns the stored energy as the heart relaxes, dampening the pulsatile pressure wave from the heart and providing continuous blood flow to distal vessels. This dampening behavior is known as the Windkessel function and when it is compromised, there are negative effects on downstream organs such as the kidneys, heart, and brain. Maturation of the arterial wall, specifically deposition of elastic fibers in the extracellular matrix, is critical for the Windkessel function. The overall goal of this research program is to determine how hemodynamic forces during embryonic development drive elastic fiber assembly and overall arterial wall maturation. The results of the research may be used to optimize clinical interventions or tissue engineering protocols that encourage proper temporal and spatial expression of extracellular matrix proteins and smooth muscle cell differentiation necessary for the Windkessel function. To date, there are no clinical interventions that can repair the Windkessel function in arterial disease or replicate the Windkessel function in tissue-engineered arterial replacements. The project will also have broader impacts through training students in research methods, exposing students to the unique growth and remodeling behavior of arteries, and introducing middle school students to engineering topics. It is generally accepted that mechanical factors, such as blood pressure and flow, influence the form and function of developing arteries, but little of the previous work has focused on the time period of arterial wall maturation. However, the maturation process is critical for the arterial Windkessel function. This project will use chick embryos to take advantage of the physical manipulation of cardiovascular hemodynamics and imaging throughout development that is uniquely possible in the chick. The role of hemodynamic forces in arterial wall maturation will be investigated through quantification of normal arterial wall maturation in the chick; quantification of altered arterial wall maturation in the chick caused by changes in blood flow and/or pressure and the resulting shear and circumferential wall stresses due to ligation of the vitelline vein; and by integrating the experimental data into a biomechanical model of arterial wall maturation that can be used for identifying critical parameters in the maturation process that may be important for clinical applications.