Session: Rising Stars of Mechanical Engineering Celebration & Showcase

Paper Number: 150039

150039 - Modulating Endothelial Cell Function Using Targeted Electrical Stimulation 

Modulating capillary barrier function within a targeted anatomic location without using systemic agents can address grand challenges in localized drug delivery. The research objective of this proposal is to investigate the effect of pulsed electric fields (PEF) on endothelial cells (EC), examining the impact on vascular permeability and elucidating signaling pathways mediating this response. Our experiments will provide proof of principle for modulating endothelial function using PEF, with future applications in cancer therapy. This proposal is closely aligned with my long-term career goal of leading a program on bioelectrics, uncovering cell and tissue response to PEF using multiscale models developed in my lab. Knowledge gained from our studies will guide the design of translational medical devices for treating tumors, and other non-malignant disease conditions. 

The endothelial lining of blood vessels regulates the passage of ions, transmits bioelectric signals, and manifests altered barrier permeability during electrical stimulation of nerves and skeletal muscles. Individually, EC are also known to exhibit galvanotaxis and angiogenesis in vitro when exposed to an electrical stimulus. Despite such diverse bioelectric behavior, EC are not conventionally considered an excitable tissue and electrical waveforms to specifically stimulate them in vivo are largely unexplored. While studying monophasic low-frequency PEF commonly used for gene delivery in humans, we identified transient increases in microvascular permeability and EC cytoskeletal remodeling. In preliminary work, we reproduced these findings using a 50 kHz biphasic PEF waveform that is minimally stimulative to skeletal muscle. Building on this foundational work, we hypothesize PEF mediated actin stress fiber remodeling in EC will transiently increase barrier permeability in monolayers from translocation of junction proteins, and trigger signaling along the Vascular Endothelial Growth Factor Receptor (VEGFR)  – adherens junction axis, where optimization of PEF parameters will improve targeted stimulation of EC.

Intellectual Merit

Targeted modulation and study of EC using electrical stimulus is a major challenge as most of our knowledge on the topic is derived from waveforms known to activate neural or muscle cells. Novel tools and mechanistic investigations that define the signaling mechanisms mediating EC responses to PEF can open several new lines of multidisciplinary investigation. We will apply unique devices and techniques developed in my lab to:

1. Define the kinetics of barrier function alterations in EC monolayers treated with PEF.

2.  Elucidate the impact of PEF on VEGFR – Vascular Endothelial-cadherin signaling.

3.  Refine PEF parameters for targeted EC stimulation and drug delivery.  

Broader Impacts 

Aberrant or dysfunctional endothelium is a hallmark of cancer and several other disease conditions. EC in the diseased tissue can interfere with therapeutic delivery, promote inflammation, and impede regeneration; underscoring the critical need for modulating its function as a key therapeutic intervention.

Presenting Author: Govindarajan Srimathveeravalli University of Massachusetts

Presenting Author Biography: Dr. Srimathveeravalli is an Asst. Professor in the Dept. of Mechanical and Industrial Engineering of Univ. Massachusetts, Amherst. Prior to joining UMass, he was a faculty In the Dept. of Radiology at Memorial Sloan Kettering Cancer Center. Dr. Srimathveeravalli is a member of the Institute for Applied Life Sciences where his lab
studies the interaction of non-ionizing energy and biology at multiscale resolution (sub-cellular – organ). Knowledge gained from experiments in his lab guides the development of medical devices and technology that will advance minimally invasive, image-guided therapy of cancer, and non-malignant diseases. Dr. Srimathveeravalli got his PhD in mechanical engineering from the University at Buffalo, and received postdoctoral training on cancer research and image-guided therapy at Memorial Sloan Kettering Cancer Center. His research has yielded over 50 peer reviewed journal articles and several chapters in textbooks. Recently he co-edited the textbook on electromagnetic energy based therapies, published by Elsevier. He is the first scientist board member of the Society for Interventional Radiology Foundation, and holds committee positions on International Society for Electroporation Based Treatments and Technologies. His research has been supported by grants from the NIH, NSF, the Society of
Interventional Radiology, Dept of Defense CDMRP program, industrial contracts, and various philanthropic foundations.

Authors:

Govindarajan Srimathveeravalli University of Massachusetts