A deficiency of uPAR alters endothelial angiogenic function and cell morphology

Neovascularization, by way of angiogenesis, involves a series of tightly regulated cellular processes. As a pathological event that is required for growth and survival of tumor cells, angiogenic signals consist of growth factors released in the microenvironment by the hypoxic tumor. These growth factors activate quiescent endothelial cells (ECs), leading to disruption of cell-extracellular matrix (ECM) contacts. Subsequently, the ECs undergo concerted changes in morphology and cytoskeletal configuration [1]. These processes enable growth factor-induced migration [2], followed by adhesion [3], proliferation, and formation of a new vascular lumen, eventually leading to development of a blood vessel [4]. The initial disruption of the EC-ECM contact requires degradation of the ECM, which is facilitated by a variety of proteases. The urokinase-plasminogen activator receptor (uPAR) binds to urokinase-plasminogen activator (uPA) [5,6], which in-turn localizes the activation of plasminogen (Pg) to the extracellular protease, plasmin (Pm) [7]. Pm then catalyzes degradation of the ECM and also activates other proteases, which together facilitate EC migration. Additionally, uPAR, by lateral interactions with its transmembrane partners, e.g., integrins [8] and low-density lipoprotein receptor-related protein (LRP), functionally orchestrates bidirectional signaling events that affect migration, adhesion, and proliferation [9]. The ability of uPAR to interact with cytoskeletal components, such as vinculin, Rac, and focal adhesion kinase (FAK), at sites of EC-ECM contacts, strongly implicates its role in cytoskeletal rearrangement [10-12].uPAR can directly interact with vitronectin (Vn), and this interaction may be enhanced by uPA, thus promoting cellular events leading to angiogenesis [8]. Several studies have shown that increased expression of uPAR, which is upregulated in different cancers [13-18], results in increased adhesion to Vn. Hence, down-regulating uPAR expression woul