Physiological electric field works via the VEGF receptor to stimulate neovessel formation of vascular endothelial cells in a 3D environment

Abstract

Electrical stimulation induces significant neovessel formation in vivo. We have shown that electrical stimulation of endothelial cells functions as an important contributor to angiogenesis in monolayer culture. Because angiogenesis occurs in a three-dimensional (3D) environment, in this study we investigated the effects of a direct current (DC) electrical field (EF) on endothelial neovessel formation in 3D culture. There was a significant increase in tube formation when endothelial cells were stimulated with EF for 4 h. The lengths of the tube-like structures were augmented further by the continued EF exposure. The lengths of the tubes also increased dose-dependently in the EF-treated cultures in the field strengths of 50 mV/mm∼200 mV/mm for 6 h. Electrical fields of small physiological magnitude enhanced VEGF expression by endothelial cells in 3D culture. EF treatment also resulted in activation of VEGFR2, Akt, extracellular regulated kinase 1,2 (Erk1/2), as well as the c-Jun NH2-terminal kinase (JNK). The tyrosine kinase inhibitor SU1498 that blocks VEGFR2 activity exhibited a potent inhibition of tube growth, and the Akt inhibitor MK-2206 2HCl, the Erk1/2 inhibitor U0126 and the JNK inhibitor SB203580 significantly reduced EF-stimulated tubulogenesis. These results suggest the importance of the VEGFR2 signaling pathway during EF-induced angiogenesis. The results of this study provide novel evidence that endogenous EFs may promote blood vessel formation of endothelial cells by activating the VEGF receptor signaling pathway.

<p>Biomimetic piezoelectric nanocomposite membranes synergistically enhance osteogenesis of deproteinized bovine bone grafts</p>

“…This may be attributed to the surface charge of the polarized nanocomposite membranes, which could stimulate vascular endothelial cell differentiation and promote neovascularization in vivo, as reported previously 41. Our results were also consistent with other studies, which showed that exogenous electrical stimulation,41,42 an external electric field,43,44 or even charged scaffold material,45 could induce vascular endothelial cell luminal formation in vitro and neovascularization in vivo. Early neovascularization had a profound effect on subsequent bone remodeling and bone maturation.…”

Direct Current Electric Field Stimulates Nitric Oxide Production and Promotes NO-Dependent Angiogenesis: Involvement of the PI3K/Akt Signaling Pathway

“…In conclusion, the present study provides evidence that a physiological level of DC EF stimulates the angiogenic phenotypes of endothelial cells via endothelial NO production, thereby extending our previous findings [18][19][20][21]. We suggest that the downstream components of the VEGF/VEGFR2 signaling pathway, PI3K/Akt-eNOS, are involved in these responses.…”

“…For example, an in vivo study by Kanno et al [16] demonstrated that electric field (EF)-stimulated contraction of skeletal muscles can lead to an increase in neovessel formation and VEGF production; Nagasaka et al [17] reported that treatment of rat skeletal muscle with low-level electrical stimulation, which does not cause contraction, was very effective in inducing significant angiogenesis. In vitro, EFs play a vital role in endothelial angiogenic processes including cell migration, elongation, alignment, and tube formation [18][19][20].…”

Electrical stimulation in bone tissue engineering treatments

“…A number of studies have been performed that test different methods of stimulating new vessel formation into the tissue engineered constructs (reviewed in [104]). Several studies, in dermal wounds, have demonstrated EStim's ability to stimulate new vessel ingrowth from pre-existing blood vessels in adjacent tissues into ischemic wounds [105][106][107][108][109]. DC EStim was shown to promote important angiogenic responses of vascular endothelial cells and selectively regulate production of growth factors and cytokines important in angiogenesis through a feedback loop mediated by VEGF receptors [110,111].…”