4. Vitronectin
4.5 Functions of vitronectin
Due to its ability to bind to several different receptors and its widespread distribution, vitronectin exerts numerous diverse biological functions. It plays an important role in the immune defense system by interacting with bacteria and by regulating the complement system. Vitronectin acts as an inhibitor of cytolytic reactions of terminal complexes of complement and of perforin210. Additionally, vitronectin serves regulating functions in the coagulation, fibrinolysis, and plasminogen activation system and thus in hemostasis206. The deposition of vitronectin associated with PAI-1 alters the balance of the fibrinolytic system to favor inhibition of fibrinolysis and development of necrosis210.
Since the focus of this study is on v3 integrin and arteriogenesis, the following part is restricted to those functions of vitronectin that are associated with this integrin or the vessel wall.
By interacting with integrin receptors, vitronectin promotes cell adhesion, spreading, and migration26. Following vitronectin binding, integrins activate diverse signaling pathways and regulate cytoskeletal reorganization, intracellular ion transport, lipid metabolism and gene expression265.
Generally, the v-subunit seems to mediate the attachment of various cells to different matrix proteins, whereas the -subunit determines the kind of interaction between cells and matrix proteins255. The 3-subunit has been shown to mediate cell migration on vitronectin and other RGD-containing substrates160,266 while v5 integrin promotes cell attachment to vitronectin267. Brown etal.25 showed that vitronectin induces v3 integrin mediated migration of human aortic SMCs and that the expression of v3 integrin is induced by TGF- and thrombin. Wilcox-Adelmann etal.268 found that ligation of v3
integrin or v5 integrin is necessary for the localization of uPAR to areas of cell-matrix adhesion and suggested that vitronectin promotes cell migration by recruiting integrin receptors and components of the PAI- system to areas of
cell-matrix contact. PAI-1 on the other hand can inhibit cell migration in vitro by competing for vitronectin binding to integrins269. Hafdi etal.270 demonstrated that adhesion of cultured human mesangial cells to vitronectin involves vß3
integrin and v5 integrin. Kanse etal.271 showed that adhesion of ECs to immobilized vitronectin is integrin-mediated without involvement of the vitronectin-uPAR-system.
Furthermore, vitronectin plays a role in tumor growth and metastasis. It has been demonstrated that the attachment, spreading, and migration response of human melanoma cells on vitronectin correlates with expression levels of v3
integrin and that these integrin levels are higher in cells from later stages of tumor progression272.
Cultured glioblastoma cells do not interact with normal brain without vitronectin but they attach to biopsy material of glioblastoma cryostat sections at sites of vitronectin expression. This implicates a role for vitronectin in metastasis of this tumor237.
Moreover, vitronectin has been related to atherogenesis in several studies.
Schoppet etal.273 showed that vitronectin and TGF- are colocalized in atherosclerotic tissues and that the binding of TGF- to vitronectin modulates either function. Naito etal.274 suggested that vitronectin is involved in atherosclerosis by recruiting SMCs from the media to the intima. Dufourq etal.154 recently found an upregulation of vitronectin after vascular injury and showed that v3 integrin and v5 integrin are required for SMC migration and that this migration as well as neointima formation can be inhibited by vitronectin blockade.
Diverse studies have additionally shown involvement of vitronectin and integrin ligation in the prevention of apoptosis. Isik etal.275 found reduced apoptosis of microvascular ECs in the presence of vitronectin with the v-subunit apparently being the critical component. Human glioma cells are protected from v3 or v5
integrin mediated, topoisomerase induced apoptosis by vitronectin276. Furthermore, Taga etal.277 showed that an antagonist of v3 integrin induces apoptosis of brain tumor cells by detaching them from vitronectin and tenascin.
Cell differentiation also seems to be partially regulated by vitronectin. The differentiation of ECs into capillary-like structures in response to vitronectin binding by v3 integrin has been shown to involve protein kinase C and phosphorylation of the receptor278. Similarly, the binding of vitronectin by guinea pig megakaryocytes via v3 integrin led to differentiation into pro-platelets279.
A study by Gawaz etal.280 suggests a contribution of vitronectin together with v3 integrin to acute myocardial infarction and reperfusion injury.
In the vascular system, Wu etal.281 showed that vitronectin and integrin binding maintains the barrier function of isolated porcine coronary venules and that the inhibition of integrin binding leads to increased venular permeability.
The role of vitronectin in atherosclerosis, neointima-formation and stenosis is controversially discussed. On one hand, Fay etal.282 showed that after chemical injury, vitronectin -/- mice display significantly shorter occlusion times than wild-type mice and that vitronectin inhibits thrombin-fibrinogen interactions. In this way, vitronectin plays an anti-thrombotic role. In accordance, de Waard etal.283 showed in a model of murine carotid artery ligation that vitronectin and PAI-1 protect against stenosis and neointima-formation as PAI-1 and vitronectin -/-mice generate a larger intima and more extensive SMC proliferation than wild-type mice.
On the other hand, Eitzmann etal.284 found that PAI-1 and vitronectin promote thrombosis in murine vessels after photochemical injury by regulating endogenous fibrinolysis. PAI-1 -/- and vitronectin -/- mice showed higher occlusion times than wild type. Similarly, Konstantinides etal.285 demonstrated that PAI-1 and vitronectin stabilize arterial thrombi in mice after chemical vascular injury and that vitronectin is accumulated after vascular injury.
Peng etal.286 showed promotion of neointima formation by vitronectin and PAI-1 in murine carotid arteries after ligation as well as after chemical injury. They suggested that this effect might be mediated by their capacity to promote fibrin deposition and to enhance SMC-fibrin interaction.
Although vitronectin exerts numerous functions, it seems not to be essential for cell adhesion and migration during mouse development and its role might overlap with other adhesive matrix components, because vitronectin-deficient mice show normal development, fertility and survival287.