title: Angiogenic effects of low-intensity cathodal direct current on ischemic diabetic foot ulcers: A randomized controlled trial.
abstract: OBJECTIVE
  This study investigated the effect of low-intensity cathodal direct current (CDC) of electrical stimulation (ES) on the release of hypoxic inducible factor-1α (HIF-1α), nitric oxide (NO), vascular endothelial growth factor (VEGF), and soluble VEGF receptor-2 (sVEGFR-2) in the wound fluid of ischemic diabetic foot ulcers (DFUs).
  
  
  METHODS
  This study was a randomized, single-blind, placebo-controlled trial. Thirty type 2 diabetes patients with ischemic foot ulcerations were randomly assigned to receive either low-intensity CDC at sensory threshold (ES group, n=15) or placebo treatment (control group, n=15) for 1h/day, 3days/week, for 4weeks (12 sessions). After debridement during the first and twelfth treatment sessions, wound fluid was collected before and after ES application to determine the levels of HIF-1α, NO, VEGF, and sVEGFR-2. Wound surface area (WSA) was measured at the first, sixth, and twelfth sessions.
  
  
  RESULTS
  At the first session, after ES application, wound-fluid levels of HIF-1α were significantly increased (+61.98pg/mL) compared to the control group (-3.85pg/mL, P=0.01). After ES application at the first and twelfth sessions, wound-fluid levels of VEGF were also significantly increased (+36.77 and +39.57pg/mL, respectively) compared to the control group (+4.15 and +0.15pg/mL, P=0.007 and P=0.019, respectively). There was no significant effect on NO and sVEGFR-2 levels between the groups.
  
  
  CONCLUSIONS
  Low-intensity CDC has positive effects on the release of HIF-1α and VEGF in the wound area of ischemic DFUs. Furthermore, our results suggest that applying ES to ischemic DFUs can be a promising way to promote angiogenesis and to achieve better outcomes in diabetic wound healing.
authors.affiliation: Department of Physical Therapy, School of Rehabilitation Sciences, Hamadan University of Medical Sciences, Hamadan, Iran; Physical Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Asadi
authors.affiliation: Physical Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address: torkamg@modares.ac.ir.
authors.forename: Giti
authors.initials: G
authors.lastname: Torkaman
authors.affiliation: Cellular and Molecular Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Hedayati
authors.affiliation: Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Mohajeri-Tehrani
authors.affiliation: Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran.
authors.forename: Mousa
authors.initials: M
authors.lastname: Ahmadi
authors.affiliation: Hajar Hospital, Tehran, Iran.
authors.forename: Roghieh Fathi
authors.initials: RF
authors.lastname: Gohardani
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D017719:Diabetic Foot / Q000628:therapy*; D004558:Electric Stimulation / Q000379:methods*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide
keywords: Diabetic foot ulcers; Electrical stimulation; HIF-1α; NO; VEGF; VEGFR-2