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7. HSPGs Enable Global Control of EC Phenotype
The ability of HS to interact with a vast number of growth factors serves to coordinate certain global phenotypes or processes. Such global trends are beginning to come to light. The endothelium of the adult is normally comprised of highly differentiated non-proliferating cells. As indicated above, the endothelial basement membrane contains high levels of HS, which sequesters a variety of heparin-binding growth factors and thereby limits their function (Fig. 3C). The importance of HS-bound growth factors stored in the basement membrane has recently been revealed by genetically engineered mice. On one hand, knock-in mice have been generated that express a HS-deficient form of perlecan, the major basement membrane HSPG. Mice expressing HS-deficient perlecan are viable but exhibit defective angiogenesis as evidenced by retarded FGF2-induced tumor growth and delayed wound healing.50 These phenotypes are observed in the context of tissue damage, where the degradation of the basement membrane normally releases HS:growth factor complexes that stimulate EC proliferation. Thus, the low levels of basement membrane HS in these mice limits the reservoir of HS-bound growth factor that can be mobilized under injury. On the other hand, transgenic mice that overexpress heparanase, the heparan cleaving enzyme, should exhibit enhanced release of HS:growth factor complexes. Indeed, such mice show increased vascularization.86 Combined, these results indicate that at least one function of HS of the endothelial basement membrane is to stimulate EC proliferation in response to tissue damage.
8. Future Therapeutic Directions
At present, HS-based therapeutics are only used for inhibition of coagulation. This application has evolved from the use of a very diverse mixture of molecules, unfractionated heparin, to the recent deployment of a pure synthetic pentasaccharide binding site for antithrombin, which is the active HS motif that conveys anticoagulant activity. The chemical synthesis of HS motifs is exceedingly complex and extremely difficult to scale up for industrial production. However, the recent cloning of HS degradation and biosynthetic enzymes should enable much more facile
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approaches that combine enzymatic and chemical methodologies. Thus, it is likely that the near future will see the therapeutic use of additional synthetic HS motifs. Potentially exploitable HS motifs should be identified through further studies of the sequence-specific nature of signaling by heparin-binding growth factors.
Given that angiogenesis is induced by the concerted action of a number of heparin-binding growth factors, this process is extremely amenable to targeting with HS-based therapeutics. Such therapeutics can serve to activate or inhibit this process. Inhibition of angiogenesis is desirable in the treatment of solid tumors, which stimulate tumor vascularization and tumor growth by secreting heparanase and heparinbinding growth factors. Optimal treatment will involve a mixture of HS motifs capable of binding specific growth factors but incapable of activating the corresponding receptors.87,88 Treatment can also include an HS motif that inhibits tumor-secreted heparanase,89 thereby preventing release of HS:growth factor complexes from the endothelial basement membrane.
Activation of angiogenesis is a potential means of treating ischemic disease by generating new blood vessels to bypass obstructed vessels. Endothelial cells downstream of an obstruction that experience hypoxia should exhibit enhanced HS levels and therefore enhanced sensitivity to growth factors. However, bypass vessel must originate upstream of the obstruction, where ECs are not hypoxic and so will likely show low responsiveness to growth factors. The need for endogenous cell surface HS can be circumvented by treating with a growth factor containing a covalently coupled HS fragment.90 Moreover, specificity for a particular receptor isoform could be defined by the sequence of the attached HS motifs. Thus, HS:growth factor hybrids potentially afford far greater specificity than non-conjugated growth factors. Such specificity may even be capable of exploiting endothelial phenotypic diversity. For example, HS:growth factor hybrids can possibly allow for targeted activation of coronary versus peripheral vessels.
9. Conclusions
The deployment of HSPGs as co-receptors superimposes multiple levels of control over signaling by heparin-binding growth factors. On the
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global level, multiple signaling pathways can be regulated by altering the level of cell surface HS, which should influence the activity of multiple heparin-binding growth factors. Conversely, the signaling capacity of individual ligand:receptor combinations may be influenced by altered biosynthesis of specific HS sequence motifs. Multiple aspects of EC biology that are regulated by specific HS-motifs should be revealed by future studies of mice deficient in various HS-sulfotransferases. Such studies may additionally reveal novel therapeutic applications for synthetic HS motifs.
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