Therapeutic Angiogenesis and Vasculogenesis for Ischemic Disease
Part I: Angiogenic Cytokines
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Deprivation of oxygen and nutrients provides a serious threat for tissue viability. Nature’s response to the development of profound tissue ischemia includes the upregulation of angiogenic growth factors and mobilization of circulating cellular elements that together enable development of an accessory vasculature.1 The involved paradigm, not surprisingly, recapitulates many aspects of embryonic circulatory development. Multiple angiogenic factors and inhibitors have been implicated in the formation and correct patterning of functional blood vessels. Although hampered by several ambiguous clinical trials, transfer of genes encoding for proangiogenic factors is still an important therapeutic option to induce vascular growth after critical ischemia. Recent studies provide further evidence that neovascularization is regulated by infiltrating circulation cells, including bone marrow–derived endothelial progenitor cells or inflammatory cells. The use of “cell therapy” for therapeutic vasculogenesis will be discussed in the second part of this review article.
Gene Therapy for Neovascularization
Candidate Genes: Experimental Evidence
Potential therapeutic genes for improvement of angiogenesis or arteriogenesis include growth factors, which predominantly act on endothelial cells to promote endothelial cell proliferation, migration, and tube-forming activity (Table 1). Concomitantly, most of the growth factors render endothelial cells less sensitive for apoptosis induction. Among the first growth factors identified to improve angiogenesis were members of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) families. Meanwhile, various isoforms of VEGF have been identified. VEGF-A and its splice variants and VEGF-B preferentially activate the VEGF receptors 1 and 2, whereas VEGF-C and VEGF-D stimulate the VEGF receptors 2 and 3, thereby contributing to lymphangiogenesis. The VEGF receptors 1 and 2 are both expressed on endothelial cells and hematopoietic stem cells. The expression of VEGF receptors on hematopoietic stem cells in particular appears to be of major importance for VEGF-dependent regulation of endothelial progenitor cells (see Part II). More recently, another member of the VEGF family, the placenta-derived growth …