Engineering a vascular endothelial growth factor 165-binding heparan sulfate for vascular therapy.
The therapeutic use of VEGF165 to stimulate blood vessel formation for the treatment of peripheral arterial disease or cardiovascular-related disease has met with limited success. Here we describe an affinity-isolated heparan sulfate glycotherapeutic (HS7(+ve)) that binds to, and enhances the bioactivity of, VEGF165. Application of HS7(+ve) complexed with VEGF165 results in enhanced VEGF165-VEGFR2 interaction, prolonged downstream pErk1/2 signalling, and increased cell proliferation and tube formation in HUVECs, compared with VEGF165 alone. The pro-angiogenic potential of HS7(+ve) was further assessed in vivo using the chick embryo chorioallantoic membrane (CAM) assay. Exogenous dosing with HS7(+ve) alone significantly enhanced the formation of new blood vessels with potencies comparable to VEGF165. These results demonstrate the potential for vascular therapy of glycotherapeutic agents targeted at augmenting the bioactivity of VEGF165.
Glycotherapeutics Group, Institute of Medical Biology, Agency for Science, Technology and Research, Singapore.
Chunming
C
Wang
Glycotherapeutics Group, Institute of Medical Biology, Agency for Science, Technology and Research, Singapore.
Selina
S
Poon
Glycotherapeutics Group, Institute of Medical Biology, Agency for Science, Technology and Research, Singapore.
Sadasivam
S
Murali
Glycotherapeutics Group, Institute of Medical Biology, Agency for Science, Technology and Research, Singapore.
Chuay-Yeng
CY
Koo
The Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand.
Tracey J
TJ
Bell
The Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand.
Simon F
SF
Hinkley
Glycotherapeutics Group, Institute of Medical Biology, Agency for Science, Technology and Research, Singapore.
Huiqing
H
Yeong
Translational Molecular Imaging Group, Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore.
Kishore
K
Bhakoo
Glycotherapeutics Group, Institute of Medical Biology, Agency for Science, Technology and Research, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University-Imperial College London, Singapore.
Victor
V
Nurcombe
Glycotherapeutics Group, Institute of Medical Biology, Agency for Science, Technology and Research, Singapore; Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Simon M
SM
Cool
D043925:Angiogenesis Inducing Agents / Q000737:chemistry / Q000494:pharmacology; D015374:Biosensing Techniques; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D006497:Heparan Sulfate / Q000737:chemistry / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods*; D015398:Signal Transduction; D014652:Vascular Diseases / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D043925:Angiogenesis Inducing Agents; D006497:Heparan Sulfate; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human
Angiogenesis; Blood vessel; Glycosaminoglycans; Heparin; VEGF; Vasculogenesis