Perivascular delivery of encapsulated mesenchymal stem cells improves postischemic angiogenesis via paracrine activation of VEGF-A

Rajesh Katare, Federica Riu, Jonathan Rowlinson, Andrew Lewis, Rachel Holden, Marco Meloni, Carlotta Reni, Christine Wallrapp, Costanza Emanueli, Paolo Madeddu*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

49 Citations (Scopus)



To test the therapeutic activity of perivascular transplantation of encapsulated human mesenchymal stem cells (MSCs) in an immunocompetent mouse model of limb ischemia.

Approach and Results

CD1 mice underwent unilateral limb ischemia, followed by randomized treatment with vehicle, alginate microbeads (MBs), MB-encapsulated MSCs (MB-MSCs), or MB-MSCs engineered with glucagon-like peptide-1. Treatments were applied directly in the perivascular space around the femoral artery. Laser Doppler and fluorescent microsphere assessment of blood flow showed a marked improvement of perfusion in the MB-MSCs and MB-MSCs engineered with glucagon-like peptide-1 groups, which was associated with increased foot salvage particularly in MB-MSCs engineered with glucagon-like peptide-1-treated mice. Histological analysis revealed increased capillary and arteriole density in limb muscles of the 2 MSC groups. Furthermore, MB-MSCs engineered with glucagon-like peptide-1 and, to a lesser extent, MB-MSC treatment increased functional arterial collaterals alongside the femoral artery occlusion. Analysis of expressional changes in ischemic muscles showed that MB-MSC transplantation activates a proangiogenic signaling pathway centered on vascular endothelial growth factor A. In contrast, intramuscular MB-MSCs caused inflammatory reaction, but no improvement of reparative vascularization. Importantly, nonencapsulated MSCs were ineffective either by intramuscular or perivascular route.


Perivascular delivery of encapsulated MSCs helps postischemic reperfusion. This novel biological bypass method might be useful in patients not amenable to conventional revascularization approaches.

Original languageEnglish
Pages (from-to)1872-1880
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number8
Publication statusPublished - Aug 2013


  • Animals
  • Disease Models, Animal
  • Feasibility Studies
  • Female
  • Femoral Artery
  • Hindlimb
  • Humans
  • Ischemia
  • Laser-Doppler Flowmetry
  • Limb Salvage
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stromal Cells
  • Mice
  • Neovascularization, Physiologic
  • Paracrine Communication
  • Random Allocation
  • Regional Blood Flow
  • Transplantation, Heterologous
  • Vascular Endothelial Growth Factor A


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