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Vascular endothelial growth factor-angiopoietin chimera with improved properties for therapeutic angiogenesis
Vascular endothelial growth factor-angiopoietin chimera with improved properties for therapeutic angiogenesis
- Source :
- Circulation
- Publication Year :
- 2013
-
Abstract
- Background— There is an unmet need for proangiogenic therapeutic molecules for the treatment of tissue ischemia in cardiovascular diseases. However, major inducers of angiogenesis such as vascular endothelial growth factor (VEGF/VEGF-A) have side effects that limit their therapeutic utility in vivo, especially at high concentrations. Angiopoietin-1 has been considered to be a blood vessel stabilization factor that can inhibit the intrinsic property of VEGF to promote vessel leakiness. In this study, we have designed and tested the angiogenic properties of chimeric molecules consisting of receptor-binding parts of VEGF and angiopoietin-1. We aimed at combining the activities of both factors into 1 molecule for easy delivery and expression in target tissues. Methods and Results— The VEGF–angiopoietin-1 (VA1) chimeric protein bound to both VEGF receptor-2 and Tie2 and induced the activation of both receptors. Detailed analysis of VA1 versus VEGF revealed differences in the kinetics of VEGF receptor-2 activation and endocytosis, downstream kinase activation, and VE-cadherin internalization. The delivery of a VA1 transgene into mouse skeletal muscle led to increased blood flow and enhanced angiogenesis. VA1 was also very efficient in rescuing ischemic limb perfusion. However, VA1 induced less plasma protein leakage and myeloid inflammatory cell recruitment than VEGF. Furthermore, angioma-like structures associated with VEGF expression were not observed with VA1. Conclusions— The VEGF–angiopoietin-1 chimera is a potent angiogenic factor that triggers a novel mode of VEGF receptor-2 activation, promoting less vessel leakiness, less tissue inflammation, and better perfusion in ischemic muscle than VEGF. These properties of VA1 make it an attractive therapeutic tool.
- Subjects :
- Vascular Endothelial Growth Factor A
capillary permeability
Angiogenesis
Vascular permeability
Neovascularization
chemistry.chemical_compound
Mice
0302 clinical medicine
Ischemia
0303 health sciences
biology
gene therapy
Angiopoietin receptor
Receptor, TIE-2
3. Good health
Hindlimb
Vascular endothelial growth factor
medicine.anatomical_structure
Leukemia, Myeloid
030220 oncology & carcinogenesis
Female
medicine.symptom
Cardiology and Cardiovascular Medicine
vascular endothelium
Blood vessel
Signal Transduction
Recombinant Fusion Proteins
Neovascularization, Physiologic
angiogenesis inducers
Mice, Inbred Strains
ischemia
Adenoviridae
Angiopoietin
Capillary Permeability
03 medical and health sciences
Physiology (medical)
Cell Line, Tumor
medicine
Angiopoietin-1
Human Umbilical Vein Endothelial Cells
Animals
Humans
Therapeutic angiogenesis
Muscle, Skeletal
030304 developmental biology
Vascular Endothelial Growth Factor Receptor-1
business.industry
Receptor Protein-Tyrosine Kinases
Genetic Therapy
Vascular Endothelial Growth Factor Receptor-2
Disease Models, Animal
HEK293 Cells
chemistry
Immunology
Cancer research
biology.protein
business
Subjects
Details
- ISSN :
- 15244539
- Volume :
- 127
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Circulation
- Accession number :
- edsair.doi.dedup.....c9e9dfde939956ba60c6a88f513a8fef