title: Efficient therapy of ischaemic lesions with VEGF121-fibrin in an animal model of systemic sclerosis.
abstract: In systemic sclerosis (SSc), chronic and uncontrolled overexpression of vascular endothelial growth factor (VEGF) results in chaotic vessels, and intractable fingertip ulcers. Vice versa, VEGF is a potent mediator of angiogenesis if temporally and spatially controlled. We have addressed this therapeutic dilemma in SSc by a novel approach using a VEGF121 variant that covalently binds to fibrin and gets released on demand by cellular enzymatic activity. Using University of California at Davis (UCD)-206 chickens, we tested the hypothesis that cell-demanded release of fibrin-bound VEGF121 leads to the formation of stable blood vessels, and clinical improvement of ischaemic lesions.
  
  
  
  Ninety-one early and late ischaemic comb and neck skin lesions of UCD-206 chickens were treated locally with VEGF121-fibrin, fibrin alone, or left untreated. After 1 week of treatment the clinical outcome was assessed. Angiogenesis was studied by immunofluorescence staining of vascular markers quantitatively analysed using TissueQuest.
  
  
  
  Overall, 79.3% of the lesions treated with VEGF121-fibrin showed clinical improvement, whereas 71.0% of fibrin treated controls, and 93.1% of untreated lesions deteriorated. This was accompanied by significantly increased growth of stable microvessels, upregulation of the proangiogenic VEGFR-2 and its regulator TAL-1, and increase of endogenous endothelial VEGF expression.
  
  
  
  Our findings in the avian model of SSc suggest that cell-demanded release of VEGF121 from fibrin matrix induces controlled angiogenesis by differential regulation of VEGFR-1 and VEGFR-2 expression, shifting the balance towards the proangiogenic VEGFR-2. The study shows the potential of covalently conjugated VEGF-fibrin matrices for the therapy of ischaemic lesions such as fingertip ulcers.
authors.affiliation: Division of Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Shadab
authors.initials: S
authors.lastname: Allipour Birgani
authors.affiliation: Division of Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Marion
authors.initials: M
authors.lastname: Mailänder
authors.affiliation: Division of Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Ines
authors.initials: I
authors.lastname: Wasle
authors.affiliation: Central Laboratory Animal Facilities, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Hermann
authors.initials: H
authors.lastname: Dietrich
authors.affiliation: Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Johann
authors.initials: J
authors.lastname: Gruber
authors.affiliation: Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.affiliation: Division of Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Roswitha
authors.initials: R
authors.lastname: Sgonc
mesh_terms: D000818:Animals; D002645:Chickens; D004195:Disease Models, Animal; D005337:Fibrin / Q000627:therapeutic use*; D009389:Neovascularization, Pathologic; D012595:Scleroderma, Systemic / Q000150:complications* / Q000473:pathology; D012883:Skin Ulcer / Q000188:drug therapy* / Q000209:etiology; D016896:Treatment Outcome; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000627:therapeutic use*
chemical_list: D042442:Vascular Endothelial Growth Factors; D005337:Fibrin; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Outcomes research; Systemic Sclerosis; Treatment