Electric fields exceeding 1 V/cm occur during wound healing, morphogenesis, and tumor growth, and such fields have been shown to induce directional migration of a variety of different cells. However, the mechanism by which electric fields direct cell movement is not yet understood, and the effects on vascular endothelial cells are entirely unknown. We demonstrate that cultured bovine aortic endothelial cells migrate toward the cathode of an applied electric field. Time-lapse microscopic imaging shows that the field suppresses protrusive activity from anode-facing surfaces of the cells while stimulating protrusions from surfaces that face the cathode. The threshold for this response is 1–2 V/cm, similar to field strengths measured in vivo. In addition, fluorescence microscopy shows that lamellipodia projecting toward the cathode are rich in actin filaments. Using quantitative image analysis, we show that the electric field induces a transient 80% increase in the amount of filamentous actin in the cell. Comparison of the distribution of F-actin with total protein distribution indicates that F-actin is asymmetrically distributed in the cytoplasm, being selectively enriched toward the cathode. We propose that physiological electric fields direct cell migration by eliciting an intracellular signal that creates new sites for actin assembly in the cathodal cytoplasm.

1.
Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27–31.
2.
McCaig CD, Zhao M: Physiological electric fields modify cell behavior. Bioessays 1997;19:819–826.
3.
Nuccitelli R: Physiological electric fields can influence cell motility, growth, and polarity. Adv Cell Biol 1988;2:213–233.
4.
Robinson KR: The response of cells to electric fields: A review. J Cell Biol 1985;101:2023–2027.
5.
Barker AT, Jaffe LF, Vanable JW Jr: The glabrous epidermis of cavies contains a powerful battery. Am J Physiol 1982;242:R358–R366.
6.
Chiang MJ, Robinson KR, Vanable JW Jr: Electrical fields in the vicinity of epithelial wounds in the isolated bovine eye. Exp Eye Res 1992;54:999–1003.
7.
Borgens RB, Vanable JW Jr, Jaffe LF: Bioelectricity and regneration: Large currents leave the stumps of regenerating newt limbs. Proc Natl Acad Sci USA 1977;74:4528–4532.
8.
Jenkins LS, Duerstock BS, Borgens RB: Reduction of the current of injury leaving the amputation inhibits limb regeneration in the red spotted newt. Dev Biol 1996;178:251–262.
9.
Borgens RB, Vanable JW Jr, Jaffe LF: Bioelectricity and regeneration: Initiation of frog limb regeneration by minute currents. J Exp Zool 1977;200:403–416.
10.
Alvarez OM, Mertz PM, Smerbeck RV, Eaglstein WH: The healing of superficial wounds is stimulated by external electrical current. J Invest Dermatol 1983;81:144–148.
11.
Borgens RB: Electrically mediated regeneration and guidance of adult mammalian spinal axons into polymeric channels. Neuroscience 1999;91:251–264.
12.
Vodovnik L, Karba R: Treatment of chronic wounds by means of electric and electromagnetic-fields. Med Biol Eng Comput 1992;30:257–266.
13.
Brighton CT, Black J, Friedenberg ZB, Esterhai JL, Day LJ, Connolly JF: A multicenter study of the treatment of non-union with constant direct current. J Bone Joint Surg 1981;63:2–13.
14.
Chang PCT, Soolik GL, Parkinson WC, Qu X, Meyer RF: Galvanotropic and glavanotaxic responses of corneal endothelial cells are inhibited by cytochalasin D and W-7. Invest Ophthalmol Vis Sci 1991;32(suppl):1219.
15.
Shuster CB, Herman IM: The mechanics of vascular cell motility. Microcirculation 1998;5:239–257.
16.
Gajdusek CM, Schwartz SM: Technique for cloning bovine aortic endothelial cells. In Vitro 1983;19:394–402.
17.
Kolega J: The movement of cell clusters in vitro: Morphology and directionality. J Cell Sci 1981;49:15–32.
18.
Coates TD, Watts RG, Hartman R, Howard TH: Relationship of F-actin distribution to development of polar shape in human polymorphonuclear neutrophils. J Cell Biol 1992;117:765–774.
19.
Stephens MA: Exact and approximate tests for directions. Biometrika 1962;49:463–477.
20.
Soong HK, Parkinson WC, Bafna S, Sulik GL, Huang, S: Movements of corneal epithelial cells and stromal fibroblasts in electric fields. Invest Ophthalmol Vis Sci 1990;31:2278–2282.
21.
Cooper MS, Schliwa M: Motility of cultured fish epidermal cells in the presence and absence of direct current electric fields. J Cell Biol 1986;102:1384–1399.
22.
Luther PW, Peng HB, Lin JJ-C: Changes in cell shape and actin distribution induced by constant electric fields. Nature 1983;303:61–64.
23.
Sulik GL, Soong HK, Chang PCT, Parkinson WC, Elner SG, Elner VM: Effects of steady electric fields on human retinal pigment epithelial cell orientation and migration in culture. Acta Ophthalmol (Copenh) 1992;70:115–122.
24.
Erickson CA, Nuccitelli R: Embryonic fibroblast motility and orientation can be influenced by phyisiological electric fields. J Cell Biol 1984;98:296–307.
25.
Yang W-P, Onuma EK, Hui S-W: Response of C3H/10T1/2 fibroblasts to an external steady electric field stimulation. Reorientation, shape change, con A receptor and intramembranous particle distribution and cytoskeletal reorganization. Exp Cell Res 1984;155:92–104.
26.
Ferrier J, Ross SM, Kanehisa J, Aubin JE: Osteoclasts and osteoblasts migrate in opposite directions in response to a constant electric field. J Cell Physiol 1986;129:283–288.
27.
Orida N, Feldman JD: Directional protrusive pseudopodial activity and motility in macrophages induced by extracellular electric fields. Cell Motil Cytoskel 1982;2:243–255.
28.
Schauble MK, Habal MB: Electropotentials of tumor tissue. J Surg Res 1969;9:517–530.
29.
Bedlack RS, Wei M-D, Loew LM: Localized membrane depolarizations and localized intracellular calcium influx during electric field-guided neurite growth. Neuron 1992;9:393–403.
30.
Zhao M, Dick A, Forrester JV, McCaig CD: Electric field-directed cell motility involves up-regulated expression and asymmetric redistribution of the epidermal growth factor receptors and is enhanced by fibronectin and laminin. Mol Biol Cell 1999;10:1259–1276.
31.
Onuma EK, Hui S-W: Electric field-directed cell shape changes, displacement, and cytoskeletal reorganization are calcium dependent. J Cell Biol 1988;106:2067–2075.
32.
Jaffe LF, Nuccitelli R: Electrical controls of development. Annu Rev Biophys Bioeng 1977;6:445–476.
33.
Keenan C, Kelleher D: Protein kinase C and the cytoskeleton. Cell Signal 1998;10:225–232.
34.
Nuccitelli R, Smart T, Ferguson J: Protein kinases are required for embryonic neural crest cell galvanotaxis. Cell Motil Cytoskel 1993;24:54–56.
35.
Brown MJ, Loew LM: Electric field-directed fibroblast locomotion involves cell surface molecular reorganization and is calcium independent. J Cell Biol 1994;127:117–128.
36.
Palmer AM, Messerli MA, Robinson KR: Neuronal galvanotropism is independent of external Ca(2+) entry or internal Ca(2+) gradients. J Neurobiol 2000;45:30–38.
37.
Djamgoz MBA, Mycielska M, Madeja Z, Fraser SP, Korohoda W: Directional movement of rat prostate cancer cells in direct-current electric field: Involvement of voltage-gated Na+ channel activity. J Cell Sci 2001;114:2697–2705.
38.
Jaffe LF: Electrophoresis along cell membranes. Nature 1977;265:600–602.
39.
den Hartigh JC, van Bergen en Henegouwen PM, Verkleij AJ, Boonstra J: The EGF receptor is an actin-binding protein. J Cell Biol 1992;119:349–355.
40.
Pullar CE, Isseroff RR, Nuccitelli R: Cyclic AMP-dependent protein kinase A plays a role in the directed migration of human keratinocytes in a DC electric field. Cell Motil Cytoskel 2001;50:207–217.
41.
O’Connor KL, Mercurio AM: Protein kinase A regulates rac and is required for the growth factor-stimulated migration of carcinoma cells. J Biol Chem 2001;276:47895–47900.
42.
Hall A: Rho GTPases and the actin cytoskeleton. Science 1998;279:509–514.
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