Mechanical Signals in Vessel Development

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This proposal outlines a three year program of research and training td establish the principal investigator (PI) as a biomedical engineering professor studying develqpmeiital cardiovascular mechanics. A postdoctoi-al year has been completed In Dr. Robert Mecham's laboratory at Washington University, where the PI expanded her knowledge of cell biology and physiology and practiced communication and management skills. The PI has accepted a tenure-track assistant professorship at Saint Louis University and plans to continue'her previous research. She will establish her independence by combining the cell biology and physiology with her expertise in biomechanics and mechanical modeling. Career training w/lir include teaching, mentorship by established professors and exposure at national meetings: During cardiovascular development, blood pressure and flow increase and smooth muscle cells produce extracellular matrix proteins, such as collagen and elastin. that define the mechanical behavior of the vessel wall. A mouse .model o( supravalvular aortic stenosis, an elastin-associated disease in humans, showed that elastin haploinsufficiency (eln+/-) results in altered vessel wall structure, decreased compliance and Increased blood pressure. Despite these features. eInW- mice live a normal life span, suggesting that they adjust to reduced elastin amounts and the resulting changes Iri rriechanicat stimuli. The hypothesis of this proposal is that developing vessels remodel to optimize mechanical stresses in the wall and that these stresses, provide a key signal for cellular differentiation. This remodeling will be described and predicted by a mathematical model in which pertiirbations cause grovi/th of various components, returning the stresses near homeostatic values. Because of the unique developmental remodeling in the eln+/-.cardiovascular system, these mice provide an Ideal tool to investigate the hypothesis and validate the mechanical model. The specific aims are: 1) To detennine hemodynamic, mechanical and geometric parameters In developing vessels. 2) To determine how changes in elastin amount alter mechanical sigriats in developing vessels. 3) To develop a constrained mixture model lo predict the growth of developing vessels.