Gene Transfer of Naked VEGF Plasmid Induces the Formation of Microvessels but not Mature Collaterals in Ischaemic Limb Muscles
Gentransfer von „nacktem” VEGF-Plasmid induziert die Bildung von Mikrogefäßen, nicht aber reifen Kollateralen in der ischämischen Extremitätenmuskulatur
J. Dulak
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorL. Partyka
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorAlicja Jozkowicz
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorG. Heba
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorM. Prager
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorCh. Neumayer
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorB. Sobhian
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorM. Thurnher
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorJ. Nanobashvili
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorA. Fügl
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorAnna Ratajska
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorP. Polterauer
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorO. Pachinger
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorF. Weidinger
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorAldona Dembinska-Kiec
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorH. Redl
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorI. Huk
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorJ. Dulak
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorL. Partyka
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorAlicja Jozkowicz
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorG. Heba
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorM. Prager
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorCh. Neumayer
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorB. Sobhian
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorM. Thurnher
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorJ. Nanobashvili
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorA. Fügl
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorAnna Ratajska
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorP. Polterauer
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorO. Pachinger
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorF. Weidinger
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorAldona Dembinska-Kiec
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorH. Redl
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorI. Huk
From the 1 Department of Clinical Biochemistry, Collegium Medicum, Krakow, Poland, the 2 Division of Cardiology, Department of Internal Medicine, University of Innsbruck, the 3 Division of Vascular Surgery, Department of Surgery, University of Vienna, the 4 Ludwig Boltzmann Research Institute for Experimental and Clinical Traumatology, Vienna, the 5 Department of Pathological Anatomy, Medical University, Warsaw, Poland, and the 6 Ludwig Boltzmann Research Institute for Interdisciplinary Vascular Medicine, Vienna
Search for more papers by this authorAbstract
enSummary: Background: Several studies have demonstrated increased numbers of angiographically detectable collaterals after vascular endothelial growth factor (VEGF) gene transfer. However, VEGF appears to be insufficient for stimulating the growth of mature blood vessels. Therefore, we decided to reinvestigate in what way the VEGF gene transfer to rabbit ischaemic muscle can restore blood flow impaired by femoral artery excision.Methods: Naked DNA, either control plasmid (pSVβgal) or pSG5-VEGF165 (harbouring human VEGF cDNA), was injected into adductor magnus muscle.Results: Human VEGF165 mRNA was detected in the ischaemic muscle injected with pSG5-VEGF165, and human VEGF protein was present in the blood plasma of the same animals but not in rabbits treated with control plasmid. However, rabbit VEGF synthesis was also enhanced in ischaemic legs of both β-gal and VEGF-treated animals. In spite of the augmented generation of endogenous VEGF, the local blood flow decreased to 75 ± 13.9 % (of flow before excision) after 28 days in pSVβgal injected animals, whereas it was preserved (97.3 ± 15 %) in pSG5-VEGF165 treated rabbits (P < 0.02). Muscles of rabbits treated with pSG5-VEGF165 showed a significantly higher number of microvessels in comparison to ischaemic muscles treated with pSVβgal (230 ± 66 vessels/mm2 vs 134 ± 48; P < 0.01), but angiographic analysis did not demonstrate significant differences in the number of collaterals between animals. Conclusions: The restoration of blood flow is most probably due to increased local angiogenesis and not to the formation of stable collateral vessels.
Abstract
deZusammenfassung: Grundlagen: Verschiedene Studien haben eine erhöhte Anzahl an angiographisch nachweisbaren Kollateralen nach Vascular Endothelial Growth Factor (VEGF)-Gentransfer nachweisen können. Allerdings scheint VEGF allein nicht ausreichend für die Ausbildung voll entwickelter Blutgefäße zu sein. Deshalb haben wir untersucht, in welcher Weise ein VEGF-Gentransfer an einem ischämischen Kaninchenmuskel die Wiederdurchblutung nach Exzision der Arteria femoralis beeinflußt.Methodik: Die „nackte” DNA, entweder als Kontrollplasmid (pSVβgal) oder pSG5-VEGF165 (humane VEGF cDNA) wurde in den Musculus adductor magnus injiziert.Ergebnisse: Humane VEGF165 mRNA konnte in dem mit pSG5-VEGF165 behandelten Muskel und humanes VEGF-Protein im Blutplasma dieser Tiere nachgewiesen werden, nicht aber in den Kaninchen, die mit dem Kontrollplasmid behandelt wurden. Allerdings war die Synthese des Kaninchen-VEGF im ischämischen Muskel sowohl in der Therapie- als auch in der Kontrollgruppe erhöht. Im Gegensatz zu der erhöhten Bildung endogenen VEGFs sank der lokale Blutfluß nach 28 Tagen auf 75 ± 13,9 % (gegenüber dem Blutfluß vor Exzision) bei den Tieren, die pSVβgal injiziert bekommen haben. Bei den Kaninchen, die mit pSG5-VEGF165 behandelt wurden, blieb der Blutfluß (97,3 ± 15 %) erhalten (P < 0,02). Die mit pSG5-VEGF165 behandelten Muskeln zeigten eine signifikant höhere Anzahl an Mikrogefäßen im Vergleich zur pSVβgal Gruppe (230 ± 66 Gefäße/mm2 vs. 134 ± 48; P < 0,01). Die angiographische Analyse zeigte keinen signifikanten Unterschied der Anzahl an Kollateralen zwischen den Gruppen.Schlußfolgerungen: Die Verbesserung der Durchblutung ist auf eine erhöhte Mikrogefäßdichte wahrscheinlich aufgrund einer stimulierten Angiogenese zurückzuführen.
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