CAREER: Modulating endothelial cell function using targeted electrical stimulation

Endothelial cells that line blood vessels become dysfunctional in cancer and several other non-malignant disease conditions, interfering with drug delivery, causing inflammation and impeding healing. However, modulating endothelial cell function at specific locations within the body without infusing drugs into the entire circulation is a major challenge. The objective of this Faculty Early Career Development Program (CAREER) proposal is to tackle this important question by developing a technology for the targeted stimulation of enendothelial cells using pulsed electric fields that can be delivered to the desired region of the body using medical devices. The project will study pulsed electric field waveforms that enable controlled and specific alteration of the endothelial cell barrier function, identify the biological pathways that mediate this response, and test this approach for enhancing drug delivery to tumors. The novel tools and knowledge gained from this proposal can enable new investigations on the role of endothelial cells in various diseases and improve treatment outcomes for millions of cancer patients. Synergistic educational and outreach activities in this proposal will develop project-based activities to create awareness in undergraduate and high school students about medical devices that use electricity as a form of therapy and to prepare them to enter the workforce or pursue higher education on the topic of medical devices. The endothelial cells (ECs) lining blood vessels regulate the passage of ions, transmit bioelectric signals, and manifest altered barrier permeability during electrical stimulation of nerves and skeletal muscles. Despite such diverse bioelectric responses, ECs have not been conventionally considered to be electrical excitable. The research objective of this proposal is to investigate whether pulsed electric fields (PEFs) can be designed to selectively stimulate ECs to alter vascular permeability, and to elucidate the signaling pathways mediating this response. The underlying hypothesis is that PEF will trigger actin stress fiber remodeling in ECs, thereby increasing capillary barrier permeability from translocation of junction proteins with signaling along the Vascular Endothelial Growth Factor Receptor (VEGFR) – adherens junction axis. In Aim 1, the kinetics of barrier function alteration in EC monolayers treated with PEF will be quantified. In Aim 2, the role of VEGFR – cadherin signaling in altering barrier permeability will be evaluated, and potential angiogenic responses studied. In Aim 3, PEF parameters will be designed for selective stimulation of ECs, and then tested for augmenting chemotherapy delivery to tumors. Novel tools and mechanistic investigations that define the signaling mechanisms mediating EC responses to PEF can open several new lines of multidisciplinary investigation and enable major advances in drug delivery. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.