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Therapuetic Essay

1072 words - 5 pages

Ischemia is a condition caused by restriction in blood supply to tissues resulting in damage or dysfunction of the tissue. Coronary, cerebral and peripheral artery atherosclerosis are the conditions that might cause tissue ischemia. Failure to treat these conditions in patients, especially in patients suffering from peripheral artery atherosclerosis, leads to intractable ischemia, impaired wound healing, ulceration and even amputation. Therapeutic angiogenesis aims at treating ischemic diseases by generating new blood vessels from existing vasculature. This is achieved by delivering exogenous factors to stimulate neovasculature formation. Induction of neovasculature provides a potential ...view middle of the document...

Other mechanisms by which VEGF promotes angiogenic effect is by recruiting already existing collaterals and by improving vasomotor function of vessels in ischemic tissue. Hypoxia and ischemia, both upregulate the expression of VEGF and VEGFR allowing a targeted therapeutic response [3]. VEGF and FGF when administered by intramyocardial, intracoronary, intrapericardial, and intravenous routes in animal models of coronary ischemia, and by intra-arterial and intramuscular routes in animal models of peripheral ischemia, these models showed potential therapeutic angiogenesis [4]. Basic Fibroblast growth factor (bFGF) when administered orally was shown to stimulate angiogenesis and rapid healing of duodenal ulcers in preclinical studies in rats [5]

Platelet-derived growth factor (PDGF) is an angiogenic growth factor, which is synthesized by many cell types in conditions like hypoxia. PDGF along with VEGF and FGF recruit vascular smooth muscle cells and pericytes to newly formed blood vessels, thus promoting vascular maturation [6].
Transcription factor, Hypoxia-inducible factor (HIF-1) mediates the physiologic response to hypoxia. In hypoxic conditions, activation of HIF-1 in eukaryotes induces expression of many genes, such as genes involved in new blood vessel formation, including isoforms of vascular endothelial growth factor and angiopoietins. Targeted expression of HIF-1 transgenes to ischemic tissues may be potential in therapeutic angiogenesis [7].
In recent years, MicroRNAs (miRNAs) are been studied as gene regulators in angiogenesis. Most miRNAs are highly expressed in endothelial cells. They are synthesized via Dicer pathway [8]. They regulate angiogenic processes. The expression of endothelial cell specific miRNA (miR-126) is seen in hematopoietic progenitor cells that are recruited to sites of ischemia during cardiac repair following infarction. This suggests that miR-126 might contribute to regenerative functions of cardiac tissue.
VEGF-A, FGF-1 and FGF-2 are the most promising and widely studied angiogenic factors. The route of administration of growth factors can be either direct or by gene based approach such as in the form of viral vector encoding the gene to be incorporated by the host endothelial cell or using naked plasmid DNA [9]. Gene therapy is useful when long-term expression of the angiogenic gene and/or tissue specific targeted therapy is desired. The dose of gene therapy is difficult to regulate since the local concentration of the angiogenic protein is highly dependent upon the level of expression of its gene. In patients, exposure of foreign genetic material and viral vectors is a...

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