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.

Objective-Electrical stimulation induces significant angiogenesis in vivo. We have shown recently that electrical stimulation induces directional migration, reorientation, and elongation of macrovascular endothelial cells. Because angiogenesis occurs mainly in the microvasculature, we have extended this observation to include human microvascular endothelial cells and compared the responses with that of vascular fibroblasts and smooth muscle cells and human umbilical vein endothelial cells. Methods and Results-Four types of vascular cells were cultured in electric fields (EFs). Dynamic cell behaviors were recorded and analyzed with an image analyzer. EFs of 150 to 400 mV/mm induced directed migration, reorientation, and elongation of all the vascular cells. HMEC-1s showed the greatest directional migration (migration rate of 11 m/h and directedness of 0.35 at 200 mV/mm). Most intriguingly, HMEC-1s migrated toward the cathode, whereas the other cell types migrated toward the anode. Conclusions-Endothelial cells derived from angiogenic microvascular as opposed to nonangiogenic macrovascular tissues were more responsive to electrical stimulation. This intriguing directional selectivity indicates that a DC electrical signal as a directional cue may be able to play a role in the spatial organization of vascular structure. Key Words: vascular cells Ⅲ electrical stimulation Ⅲ angiogenesis Ⅲ heterogeneity Ⅲ cell migration Ⅲ alignment Ⅲ orientation M odulation of new blood vessel formation, either to increase the blood supply to ischemic tissue or to inhibit blood supply to undesired neoplasm such as cancer, offers great hope for treatment of a vast spectrum of diseases. 1 Electrical stimulation has emerged recently as a novel approach to induce angiogenesis in vivo, and this is mediated by enhanced local expression of vascular endothelial growth factor (VEGF) by muscle cells. [2][3][4] More recently, we and others have shown that electrical stimulation also has significant direct effects on endothelial cells to induce reorientation of the long axis of the cell, directional cell migration, and to stimulate cell elongation. [5][6][7][8] This may be of physiological significance because endogenous electric fields (EFs) have been found to be associated with circulation, tissue damage, and abnormal cell proliferation. 9 -14 Endogenous EFs are widespread, have been measured directly in animals and in humans, and may be important for development and wound healing. [15][16][17] For example, a steady DC EF of 450 to 1600 mV/mm has been measured across the wall of the amphibian neural tube during early neuronal development, 16 and disrupting this perturbs neural development. 18 At surface wounds, a steady DC EF of at least 40 mV/mm in bovine cornea and 100 to 200 mV/mm in guinea pig skin arises as soon as the wound occurs, and this persists until re-epithelialization is complete. 19 -21 This laterally oriented EF is attributable to the immediate flow of current driven by the transepithelial potential difference, which is susta...

Small direct current (DC) electric fields direct some important angiogenic responses of vascular endothelial cells. Those responses indicate promising use of electric fields to modulate angiogenesis. We sought to determine the regulation of electric fields on transcription and expression of a serial of import angiogenic factors by endothelial cells themselves. Using semi-quantitative PCR and ELISA we found that electric stimulation upregulates the levels of mRNAs and proteins of a number of angiogenic proteins, most importantly VEGF165, VEGF121 and IL-8 in human endothelial cells. The up-regulation of mRNA levels might be specific, as the mRNA encoding bFGF, TGF-beta and eNOS are not affected by DC electric stimulation at 24 h time-point. Inhibition of VEGF receptor (VEGFR1 or VEGFR2) signaling significantly decreased VEGF production and completely abolished IL-8 production. DC electric stimulation selectively regulates production of some growth factors and cytokines important for angiogenesis through a feed-back loop mediated by VEGF receptors.

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Patients with PCOS with HA have higher oxidative stress levels compared with those without HA. The increased oxidative stress in PCOS is related to HA status, increased plasma glucose, TG, HDL-C and E levels, decreased apoA1 concentrations and a relative shortage of antioxidant capacity.