Christoph Brenner1, Nicolle Kränkel2, Sarah Kühlenthal3, Lars Israel4, Friederike Remm3, Cornelia Fischer3, Nadja Herbach5, Timo Speer6, Ulrich Grabmaier3, Alexandra Laskowski3, Lisa Gross3, Hans Theiss3, Rüdiger Wanke5, Ulf Landmesser2, Wolfgang-Michael Franz7. 1. Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany; Institute of Physiology, Cardiovascular Research, University of Zurich, Campus Irchel, Zurich, Switzerland; Department of Internal Medicine III, Medical University Innsbruck, Innsbruck, Austria. Electronic address: mail@med.cbrenner.net. 2. Department of Cardiology, University Hospital Zurich, Zurich, Switzerland; Institute of Physiology, Cardiovascular Research, University of Zurich, Campus Irchel, Zurich, Switzerland. 3. Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany. 4. Institute of Molecular Biology, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany. 5. Institute of Veterinary Pathology, Ludwig-Maximilians-University, Munich, Germany. 6. Institute of Physiology, Cardiovascular Research, University of Zurich, Campus Irchel, Zurich, Switzerland; Department of Internal Medicine IV, Saarland University Hospital, Homburg/Saar, Germany. 7. Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany; Department of Internal Medicine III, Medical University Innsbruck, Innsbruck, Austria. Electronic address: wolfgang-michael.franz@uki.at.
Abstract
BACKGROUND: Endothelial injuries regularly occur in atherosclerosis and during interventional therapies of the arterial occlusive disease. Disturbances in the endothelial integrity can lead to insufficient blood supply and bear the risk of thrombus formation and acute vascular occlusion. At present, effective therapeutics to restore endothelial integrity are barely available. We analyzed the effect of pharmacological DPP-4-inhibition by Sitagliptin on endogenous progenitor cell-based endothelial regeneration via the SDF-1α/CXCR4-axis after acute endothelial damage in a mouse model of carotid injury. METHODS AND RESULTS: Induction of a defined endothelial injury was performed in the carotid artery of C57Bl/6 mice which led to a local upregulation of SDF-1α expression. Animals were treated with placebo, Sitagliptin or Sitagliptin+AMD3100. Using mass spectrometry we could prove that Sitagliptin prevented cleavage of the chemokine SDF-1α. Accordingly, increased SDF-1α concentrations enhanced recruitment of systemically applied and endogenous circulating CXCR4+ progenitor cells to the site of vascular injury followed by a significantly accelerated reendothelialization as compared to placebo-treated animals. Improved endothelial recovery, as well as recruitment of circulating CXCR4+ progenitor cells (CD133+, Flk1+), was reversed by CXCR4-antagonization through AMD3100. In addition, short-term Sitagliptin treatment did not significantly promote neointimal or medial hyperplasia. CONCLUSION: Sitagliptin can accelerate endothelial regeneration after acute endothelial injury. DPP-4 inhibitors prevent degradation of the chemokine SDF-1α and thus improve the recruitment of regenerative circulating CXCR4+ progenitor cells which mediate local endothelial cell proliferation without adversely affecting vessel wall architecture.
BACKGROUND: Endothelial injuries regularly occur in atherosclerosis and during interventional therapies of the arterial occlusive disease. Disturbances in the endothelial integrity can lead to insufficient blood supply and bear the risk of thrombus formation and acute vascular occlusion. At present, effective therapeutics to restore endothelial integrity are barely available. We analyzed the effect of pharmacological DPP-4-inhibition by Sitagliptin on endogenous progenitor cell-based endothelial regeneration via the SDF-1α/CXCR4-axis after acute endothelial damage in a mouse model of carotid injury. METHODS AND RESULTS: Induction of a defined endothelial injury was performed in the carotid artery of C57Bl/6 mice which led to a local upregulation of SDF-1α expression. Animals were treated with placebo, Sitagliptin or Sitagliptin+AMD3100. Using mass spectrometry we could prove that Sitagliptin prevented cleavage of the chemokine SDF-1α. Accordingly, increased SDF-1α concentrations enhanced recruitment of systemically applied and endogenous circulating CXCR4+ progenitor cells to the site of vascular injury followed by a significantly accelerated reendothelialization as compared to placebo-treated animals. Improved endothelial recovery, as well as recruitment of circulating CXCR4+ progenitor cells (CD133+, Flk1+), was reversed by CXCR4-antagonization through AMD3100. In addition, short-term Sitagliptin treatment did not significantly promote neointimal or medial hyperplasia. CONCLUSION:Sitagliptin can accelerate endothelial regeneration after acute endothelial injury. DPP-4 inhibitors prevent degradation of the chemokine SDF-1α and thus improve the recruitment of regenerative circulating CXCR4+ progenitor cells which mediate local endothelial cell proliferation without adversely affecting vessel wall architecture.
Authors: Michael E Widlansky; Venkata K Puppala; Tisha M Suboc; Mobin Malik; Amberly Branum; Kara Signorelli; Jingli Wang; Rong Ying; Michael J Tanner; Sudhi Tyagi Journal: Vasc Med Date: 2017-02-01 Impact factor: 3.239
Authors: Bárbara Torrecillas-Baena; María Ángeles Gálvez-Moreno; José Manuel Quesada-Gómez; Gabriel Dorado; Antonio Casado-Díaz Journal: Stem Cell Rev Rep Date: 2021-10-22 Impact factor: 5.739
Authors: Calinda K E Dingenouts; Wineke Bakker; Kirsten Lodder; Karien C Wiesmeijer; Asja T Moerkamp; Janita A Maring; Helen M Arthur; Anke M Smits; Marie-José Goumans Journal: PLoS One Date: 2017-12-18 Impact factor: 3.240