Endothelial cell injury is considered the initiating event in atherosclerotic plaque development and cardiovascular disease, the leading cause of mortality in the United States. In a healthy blood vessel, endothelial cells regulate vascular function in a complex three-dimensional environment. Cells dynamically integrate biochemical and mechanical stimulation from the flowing blood at their apical surface and the basement membrane at their basolateral surface. Disruptions in the biochemical environment, such as elevated glucose, and disturbances in the mechanical environment, such as low shear stress, contribute to endothelial cell dysfunction and subsequent cardiovascular disease. People with diabetes develop accelerated atherosclerosis at low shear stress locations, suggesting that biochemistry and biomechanics may interact through common signaling pathways.
The research objective of this project is to use glucose-induced alterations in endothelial cells and basement membrane to investigate integrated biochemical (growth factor) and biomechanical (shear stress) interactions within the endothelial cell basement membrane co-regulatory unit. This research will be conducted in a three-dimensional experimental system, in which shear stress can be applied to endothelial cell populations (microfluidics) or single cells (dielectrophoretic device) on defined basement membrane substrates.
This research integrates biochemistry and biomechanics in the vascular wall. The project will develop quantitative relationships describing how growth factors are regulated in mechanical conditions, how basement membrane properties are altered by shear stress and high glucose, and how these basement membrane changes affect the endothelial cell mechanical response. Understanding of integrated, three-dimensional vascular biology will be enhanced, and this new knowledge can then be used to develop targeted pharmaceutical therapies that decrease cardiovascular morbidity and mortality. Furthermore, this integrative model of cell and extracellular matrix can be translated across diverse cell types to improve the physiological relevance of a wide variety of in vitro studies. In the United States, cardiovascular disease accounts for 65% of deaths in people with diabetes. With diabetes prevalence and disease duration on the rise, research into the pathophysiology of cardiovascular disease and diabetes could alleviate this predicted healthcare burden.
The PI will integrate research with educational programs that explore current challenges at the interface of engineering and life sciences and create connections among students, faculty, and the community. The educational objective of this project is to inspire students, especially women and underrepresented minorities, to explore engineering careers by providing biomedical discovery opportunities coupled with intergenerational mentoring. Outreach programs will use one of the most fascinating engineering systems, the human body, to demonstrate to students from diverse backgrounds how engineers can help solve societal challenges.
