Toloo Taghian, Abdul Sheikh, Andrei Kogan and Daria Narmoneva
Biomedical Engineering, University of Cincinnati, Cincinnati, OH, USA
BACKGROUND
Regeneration of vascular tissues is a necessary component for development of effective therapies for impaired healing of vascular tissues, for example, to address significant health care problems associated with fibrotic myocardial remodeling & chronic ulcers. Impaired healing in vascular tissues is characterized by altered tissue microenvironment, unbalanced proteolytic activity, prolonged inflammation and insufficient neovascularization. External electric field (EF) can affect a variety of vascular cell responses through manipulation of native EF in the extracellular ionic environment and across the cell membrane. Therefore, EF, together with the extracellular matrix (ECM) and a milieu of cytokines represent a biophysical system that ultimately regulates vascular cell function. Therapeutic modulation of this system requires advanced integration of knowledge and technology of physics and biomedical sciences. Our research aims to elucidate the biophysical mechanisms of cell-EF interactions mediated by ECM through developing a theoretical-experimental approach. Theoretical 3D EF-cell interaction model solves Maxwell’s equations (ANSOFT_HFSS) for a membrane-enclosed hemisphere subjected to EF to provide a precise distribution of induced EF within the cell in wide frequency range. Simulations demonstrate that, at low frequency, EF is confined in the cell membrane and is expected to regulate membrane-initiated responses only. At high frequency, EF penetrates the cell and may directly activate intracellular responses. These predictions are confirmed by our experimental results, which demonstrate a major role for cRaf/MEK/ERK and Ca2+pathways in EF-mediated stimulation of angiogenic responses. The results show that cell responses to EF differ in natural versus synthetic ECM. These findings provide evidence for a novel mechanism of EF-mediated regulation of vascular cell interactions within the complex biophysical system. In vivo, this mechanism translates into increased wound vascularization and improved healing, and therefore, provides foundation for development of EF-based therapies for vascular tissue regeneration.
These studies were supported byNIH/NDDK R21DK078814 (DN), AHA BGIA- 533 0765425B (DN), N.S.F. (DMR-1206784) and (DMR 0804199) to AK.