Thrombospondin­4 (TSP-4) is an ~140kD matricellular protein that is secreted as a disulfide­linked pentamer. Within the Thrombospondin family, TSP­3 and TSP­5/COMP are also pentameric, while TSP­1 and TSP­2 are trimeric. TSP­4 regulates cell­cell and cell matrix interactions and plays a role in cardiovascular physiology and neuronal development (1, 2). Mature mouse TSP-4 consists of an N­terminal heparin­binding domain, a coiled coil motif, four EGF­like repeats, seven TSP type­3 repeats (one with an RGD motif), and a TSP C­terminal domain (2, 3). Mouse TSP-4 shares 93% and 97% amino acid sequence identity with human and rat TSP-4, respectively. TSP-4 binds a variety of matrix proteins including Collagens I, II, III, V, Laminin­1, Fibronectin, and Matrilin­2 (4). Interactions of TSP-4 with non­collagenous proteins are independent of divalent cations, whereas interactions with collagenous proteins are enhanced in the presence of zinc (4). TSP-4 binds to cell surface Integrins containing the alphaM, beta2, or beta3 chains (5, 6). It is expressed in skeletal muscle and tendon as well as by vascular smooth muscle and endothelial cells (7­9). It is up­regulated in cardiomyocytes during pressure overload and is required for mediating the responsive increase in cardiac contractility (10). In humans, a polymorphism of TSP­4 (A387P) is associated with myocardial infarction (11). TSP-4 contributes to the development of inflammation and atherosclerosis by promoting macrophage and neutrophil adhesion to the vasculature (5, 6). In the nervous system, TSP-4 is expressed by astrocytes and neurons and is enriched at neuromuscular junctions and synapse­rich layers of the brain and retina (9, 12, 13). It promotes neuronal adhesion, neurite outgrowth, and excitatory synaptogenesis (9, 13, 14). TSP-4 is up­regulated in the spinal cord following peripheral nerve injury where it contributes to presynaptic hypersensitivity and hyperalgesia (12). It is also up­regulated in muscle following denervation (9). TSP-4 is additionally secreted by tumor­associated fibroblasts in gastric adenocarcinoma, particularly in regions of tumor cell invasion (15).