Is Syndecan-2 a Key Angiogenic Element?

Angiogenesis has been extensively related with the development of many different diseases, from tumor progression to cardiovascular disorders. In our last article, we demonstrated that syndecan-2, the most abundant heparan sulfate proteoglycan expressed by human microvascular endothelial cells, is regulated by proangiogenic factors and plays an important role in most of the cellular events that take place in neovascularization processes. Here, we also reported its involvement in the reorganization of the cytoskeleton and propose a key role for this proteoglycan as an adaptor protein, able to work in cooperation with the integrins in the formation of new blood vessels.

described the interaction of the PDZ protein Ezrin with the proximal part of the cytoplasmic domain of syndecan-2, and that its overexpression in COS cells induces filopodia through cdc42 activation [26]. We also described how its overexpression in epithelial cells induces a migratory phenotype [27] and stimulates the proliferation in Swiss 3T3 fibroblasts [28]. In addition, other researchers found the same results on colon carcinoma cells [16,17].
In our last study, by down-regulation of syndecan-2 expression with phosphorothioate antisense oligonucleotides in a human endothelial microvascular cell model, we demonstrated its involvement in different cellular functions related to angiogenic processes [22]. We showed that it decreases the spreading and adhesion of these cells when seeded on fibronectin, increased its migration, but impaired the formation of capillary-like structures in matrigel. Additional experiments also demonstrated that the inhibition of this proteoglycan decreased and reorganized the focal adhesions, as shown by paxillin immunostaining, while increasing the stress fibers assembly (Fig. 1). This is consistent with a migratory phenotype, but also with an impairment of the endothelial morphogenesis into tubular structures [29]. We also demonstrated that syndecan-2 protein expression is specifically regulated by well-known proangiogenic growth factors, such as FGF or VEGF, and also different matrices, such as fibronectin or collagen, both in two-or three-dimensional culture conditions. Typically, an enrichment in fibronectin is seen under wound healing conditions, and laminin and collagen deposition has been described for certain tumors [30,31]. As these processes are also characterized by an enhanced release of growth factors and both conditions are able to induce syndecan-2 expression, these proteoglycans may play a pivotal role in giving the adequate response in each situation.
Evidence for integrin and syndecan cooperation in signaling events has become clear in recent years [8], since the regulation of the α v β 3 and α v β 5 integrins by syndecan-1 during angiogenesis has been demonstrated [32], as well as the interaction with Mac-1 [33]. Furthermore, syndecan-2 is able to interact with α 5 β 1 integrin in the regulation of stress fiber formation [34], and with α 2 integrin [35] in the control of adhesion and migration. On the other hand, syndecan-2 has also been involved in signaling processes, as in the phosphorylation of FAK [36] or in the activation of src, when this proteoglycan is in complex with p120-GAP [37].
Taking all these considerations together with our results that demonstrated the involvement of syndecan-2 in most of the basic events that take place during neovascularization in endothelial cells cultured "in vitro" [22], we propose a role for this proteoglycan as an adaptor protein that is able to integrate different environmental signals essential to induce the angiogenic switch through the regulation of its expression, and a key element in cooperation with the integrins in order to induce cytoskeleton reorganization necessary for capillary morphogenesis.
Although its importance has not been fully elucidated, as it may also be needed in other processes, such as matrix degradation by metalloproteases or in apoptosis, our work helps to clarify the role of this heparan sulfate proteoglycan in the biology of endothelial cells. Further "in vivo" experiments may determine if it would be a good target for antiangiogenic therapies, one of the most promising antitumor strategies [38], but also for many other diseases.