TY - JOUR
T1 - Therapeutic angiogenesis of mouse hind limb ischemia by novel peptide activating GRP78 receptor on endothelial cells
AU - Hardy, Britta
AU - Battler, Alexander
AU - Weiss, Chana
AU - Kudasi, Orly
AU - Raiter, Annat
PY - 2008/2/15
Y1 - 2008/2/15
N2 - Therapeutic angiogenesis emerged as a non-invasive mean of promoting neovascularization in ischemic tissues. We have searched for new molecules that induce angiogenesis by screening a phage display combinatory peptide library on endothelial cells. One of the selected peptides identified by binding to endothelial cells under hypoxic conditions was further studied. The aim of this study was to assess the therapeutic value of this peptide, RoY, in a mouse hind limb ischemia model and to identify it's receptor on endothelial cells. RoY, a 12 amino-acid synthetic peptide, induced in vitro angiogeneic activity under hypoxic conditions by increasing endothelial cell proliferation, migration and tube formation. In order to assess its therapeutic properties in ischemic tissues, a hind limb ischemia model was induced in C57BL mice by a femoral artery excision. A single local intramuscular injection of RoY peptide to the operated limb, significantly restored blood perfusion and alleviated hind limb ischemia as determined by a laser Doppler imager. Increased capillary density in histological sections corroborated these findings. Protein precipitation and mass spectroscopy studies identified GRP78, a heat shock protein, as the peptide-binding membrane receptor that was increased on endothelial cell membranes under hypoxic conditions. This study demonstrates the efficacy of RoY peptide in alleviation of hind limb ischemia. In addition, it provides evidence that GRP78 is an angiogenic receptor on hypoxic endothelial cells.
AB - Therapeutic angiogenesis emerged as a non-invasive mean of promoting neovascularization in ischemic tissues. We have searched for new molecules that induce angiogenesis by screening a phage display combinatory peptide library on endothelial cells. One of the selected peptides identified by binding to endothelial cells under hypoxic conditions was further studied. The aim of this study was to assess the therapeutic value of this peptide, RoY, in a mouse hind limb ischemia model and to identify it's receptor on endothelial cells. RoY, a 12 amino-acid synthetic peptide, induced in vitro angiogeneic activity under hypoxic conditions by increasing endothelial cell proliferation, migration and tube formation. In order to assess its therapeutic properties in ischemic tissues, a hind limb ischemia model was induced in C57BL mice by a femoral artery excision. A single local intramuscular injection of RoY peptide to the operated limb, significantly restored blood perfusion and alleviated hind limb ischemia as determined by a laser Doppler imager. Increased capillary density in histological sections corroborated these findings. Protein precipitation and mass spectroscopy studies identified GRP78, a heat shock protein, as the peptide-binding membrane receptor that was increased on endothelial cell membranes under hypoxic conditions. This study demonstrates the efficacy of RoY peptide in alleviation of hind limb ischemia. In addition, it provides evidence that GRP78 is an angiogenic receptor on hypoxic endothelial cells.
KW - Angiogenesis
KW - Endothelial cells
KW - GRP78
KW - Hypoxia
KW - Ischemia
KW - Peptides
UR - http://www.scopus.com/inward/record.url?scp=38649085349&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2007.10.008
DO - 10.1016/j.bcp.2007.10.008
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 18022603
AN - SCOPUS:38649085349
SN - 0006-2952
VL - 75
SP - 891
EP - 899
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 4
ER -