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Therapeutic angiogenesis for ischemic syndromes
1Department of Cardiology, Lady Davis Carmel Medical Center, Haifa, Israel.
Insights
Gene therapy using adenoviral vectors effectively delivers vascular endothelial growth factor (VEGF) to promote angiogenesis. This approach enhances endothelial cell proliferation, offering a potential new treatment for arterial obstructive disease.
Area of Science:
- Cardiovascular Biology
- Gene Therapy
- Vascular Biology
Background:
- Atherosclerosis is a leading cause of death, with limited treatment options for patients unsuitable for angioplasty or surgery.
- Enhancing collateral circulation is crucial for improving blood flow to ischemic tissues.
Purpose of the Study:
- To evaluate the efficacy of adenoviral vectors for gene transfer of vascular endothelial growth factor (VEGF).
- To assess VEGF-mediated angiogenesis in human vascular cells in vitro and in vivo.
Main Methods:
- Adenoviral vectors encoding lacZ and VEGF (rAdlacZ, rAdVEGF) were used to infect human saphenous vein endothelial and smooth muscle cells.
- VEGF expression and biological activity were analyzed using Western blot and proliferation assays.
- In vivo gene transfer feasibility was assessed via direct femoral artery injection of rAdlacZ in rats.
Main Results:
- Adenoviral vector-mediated VEGF expression was confirmed in infected human vascular cells.
- VEGF significantly increased endothelial cell proliferation by threefold compared to controls.
- Successful in vivo gene transfer of lacZ to arterial wall cells was demonstrated in rats.
Conclusions:
- Adenoviral vectors provide efficient gene delivery both in vitro and in vivo.
- VEGF overexpression via gene therapy promotes endothelial cell proliferation, a key step in angiogenesis.
- This strategy holds promise for developing less invasive treatments for arterial obstructive diseases.
Abstract:
Disease caused by atherosclerosis are the most common causes of morbidity and mortality in western societies. The inadequacy of current therapeutic modalities is most pronounced in the significant proportion of patients with arterial obstructive disease, in whom anatomical and technical limitations rule out the possibility of angioplasty or surgery. Therefore, less invasive approaches are necessary to treat these patients. The development of collateral circulation improves blood flow to ischemic tissues and to alleviate ischemia-related symptoms. Our project concentrates on enhancement of the natural mechanism of angiogenesis by adenoviral based vector encoding vascular endothelial growth factor as an angiogenic factor. The aim of our study was to determine the efficacy of human vascular cell infection by adenoviral based vectors in vitro and in vivo. Human saphenous vein endothelial cells and smooth muscle cells were infected by adenoviral vectors encoding the lacZ and VEGF genes (rAdlacZ, rAdVEGF). VEGF expression by adenoviral vector-infected cells was detected by western analysis and its biological activity was examined by proliferation assay. The feasibility of adenoviral based gene transfer in vivo was evaluated after direct femoral artery injection of rAdlacZ in the rat. Vascular endothelial and smooth muscle cells expressed high levels of VEGF following rAdVEGF infection. The mitogenic effect of VEGF was validated by threefold increase in EC proliferation rate in comparison to the control groups. In vivo gene transfer was demonstrated using lacZ gene transfer to arterial wall cells in the superficial femoral artery. Efficient adenoviral based gene delivery was demonstrated both in vitro and in vivo. VEGF over-expression enhanced endothelial cell proliferation, which is the key step for induction of angiogenesis.