Electrical stimulation directly induces pre-angiogenic responses in vascular endothelial cells by signaling through VEGF receptors

Abstract

Controlling angiogenesis is crucial. Growth factors and cytokines are key regulators but a full understanding remains elusive. Endogenous electrical potential differences exist within and around the vasculature, both in relation to blood flow and in situations where active angiogenesis occurs, such as wound healing, development and tumor growth. Recent work shows that electrical stimulation induces significant angiogenesis in vivo, through enhanced vascular endothelial growth factor (VEGF) production by muscle cells. We report that applied electric fields (EFs) of small physiological magnitude directly stimulate VEGF production by endothelial cells in culture without the presence of any other cell type. EFs as low as 75–100 mV mm−1 (1.5–2.0 mV across an endothelial cell) directed the reorientation, elongation and migration of endothelial cells in culture. These pre-angiogenic responses required VEGF receptor activation and were mediated through PI3K-Akt and Rho-ROCK signaling pathways, resulting in reorganization of the actin cytoskeleton. This indicates that endogenous EFs might play a role in angiogenesis in vivo by stimulating the VEGF receptor signaling pathway, to induce key pre-angiogenic responses. In addition, it raises the feasibility of using applied EFs to initiate and guide angiogenesis through direct effects on endothelial cells.

Interactive effects of surface topography and pulsatile electrical field stimulation on orientation and elongation of fibroblasts and cardiomyocytes

“…The PI3K pathway was documented to regulate a number of physiological functions, including cell growth, survival and actin cytoskeleton rearrangement [57]. It was documented to be involved in a physiological hypertrophy of cardiomyocytes [58,59] as well as in the response of endothelial cells [60], keratinocytes and epithelial cells to stimulation with DC fields [61]. In activated platelets, PI3-kinase associates with cytoskeleton when significant actin polymerization occurs [62].…”

“…Yet pulsatile field stimulation was able to reverse this effect ( Figure 6C, D), indicating that a parallel pathway may be involved in transduction of the electrical stimulation signals. Zhao et al [60] documented that in addition to PI3 kinase pathway, Rho kinase pathway was involved in the response of endothelial cells to DC filed stimulation. However, LY294002 treated monolayers could not contract synchronously in response to electrical field stimulation, although both actin cytoskeleton ( Figure 8) and sarcomeres ( Figure 7) were identified, an observation consistent with our previous findings on cardiac tissue constructs [9].…”

Effect of low voltage AC fields on cardiovascular implants

“…Szmitko et al [8] argued that prior harvesting of endothelial cells on the prosthetic conduit is labour intensive and time consuming, furthermore it may cause distortion of the cell phenotype [8]. Zhao et al [9] derived a theory that electrical stimulation directly induces angiogenic responses that promotes enhanced production of Vascular Endothelial Growth Factors (VEGF). This is because cells are enclosed by a cell membrane which consists of an ionic solution.…”

Harnessing the Electric Spark of Life to Cure Skin Wounds

“…Although the mechanisms of vascular remodeling are as yet incompletely understood, initial evidence indicates that physiological EFs induce angiogenic responses in endothelial cells which are mediated by both the VEGF receptor and PI3K. 54 PTEN has been identified as a negative regulator of angiogenesis. 55 Therefore, PTEN inhibition would potentially be advantageous to enhance EF-mediated angiogenesis and wound repair responses in diabetic patients.…”