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6.2. Genetic determination of neovascularization
Recent advances in molecular medicine led us to take into account the genetic aspect of the neovascularization response. Increasing evidence shows that genetic background and related predisposed conditions can affect neovascular development. Genetic loci which can influence angiogenic responses induced by VEGF or FGF2 were mapped in the mouse genome, suggesting that variation of the genetic background plays a role in determining the angiogenic responsiveness. Moreover, a number of sporadic mutations and polymorphisms which can alter angiogenic response have also been identified.29 In contrast to mutations which in general affect health to a greater extent, smaller genetic changes often referred to as polymorphism do not manifest overt phenotypes and are much more common in the human population. Among them VEGF polymorphisms in the promoter region which are implicated in a wide variety of angiogenesis-dependent diseases can predispose to a person the altered neovascularization response. Making an allowance for anatomic severity and duration of disease, clinical observations have long noted a variable presence or absence of collateral circulation on coronary angiograms. Of particular interest is the ability of monocytes from different individuals to respond to hypoxia by increasing HIF-1α expression correlated with the extent of collateral development.30 Although the degree of collaterarization is independent of plasma levels of proor anti-agniogenic factors, monocytes functionality discriminates patients with different degree of collateral development, suggesting genetic differences in the patient population.31 In an extension of this idea, a further study has identified, using monocyte transcriptomes from CAD patients with and without well developed collaterals, a set of molecular markers characteristic of a “non-collateralgenic” phenotype.32
7. Future Prospective
One of the fundamentally new approaches to therapeutic angiogenesis is to improve tissue responsiveness to angiogenic stimuli. To achieve this goal, more research efforts need to be focused on basic research
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to investigate what determines angiogenic responsiveness. Endothelial function is probably of prime importance to determine the course of neovascularization as the initial response of endothelial cells plays a key role in the angiogenic and arteriogenic processes. The other key cell type is a monocyte or an EPC. Recently, circulating EPCs have been shown to correlate inversely with the risk of cardiovascular events.33,34 Hypercholesterolemia has been shown to delay arteriogenic process by affecting monocyte function.35 A similar observation has been made in diabetic patients.36 By analogy with coronary risk factors, we may be able to identify neovascularization risk factors as these two conditions often co-exist in the patient population.
We also need to explore the contribution of the genetic background in the neovascularization process since it will enable us to estimate neovascularization potential and predict the efficacy of the therapy. While this custom-made approach requires careful dissection of patient population according to the various genetic backgrounds underlying the ischemic disease, it undoubtedly shows great promise for the future. For example, in the case of a polymorphism that reduces the VEGF promoter activity, the supplement of VEGF may be beneficial. Furthermore, we may be able to utilize genetically modified monocytes and EPCs depending on the abnormality in the patients’ genetic program.
Whatever strategy we use in therapeutic angiogenesis, it is essential to expand our knowledge on arterial development as an arteriogenesis approach will be the mainstream of therapeutic angiogenesis in the future. With regard to the mechanism of arteriogenesis, we still do not know what the most important driving force is and whether larger arteries can be formed de novo in adult humans. In the embryonic development, circulatory dynamics were previously thought to play a major role in establishing arterial-venous determination; however, recent molecular analyses have demonstrated the underlying process of this specification.37 It has been clear that arterial and venous endothelial cells are molecularly distinct even before the initiation of the first embryonic heartbeat, revealing the existence of genetic programs coordinating arterial-venous differentiation. Recent studies have identified VEGF, Notch, and Ephrin/Eph signaling as critical factors determining arterial and venous cell fate.
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8. Summary
Therapeutic modulation of angiogenesis is still at its infant stages, but it is showing considerable potential. The ultimate success of this therapeutic modality will depend on careful translation of research programs that will incorporate the ever-evolving basic understanding of the biology of neovascular development into effective, adequately powered clinical trial programs. The likely keys include the careful choice of a biological agent that may be different for different indications, effective delivery modality with pharmacokinetic properties matching biological needs, and the meticulous choice of patient population and end-points for the study. While still controversial, cell therapy has an enormous potential that is yet to be explored. In addition, with the advance of basic research, different strategies for therapeutic angiogenesis have come into view that can fundamentally change our approach to this issue. These include increasing tissue neovascularization responsiveness and genetic analysis of neovascularization potentials. Therefore, new developments will be expected in this area in the next decade enabling us to treat better end-stage ischemic diseases.
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