Tetraspanin-18, also known as TSPAN18 (TSN18), is a member of the Tetraspanins (Tspans) family of four-span transmembrane proteins. The TSPAN18 gene may be involved in the development of psychotic symptoms and contributes to clinical heterogeneity of schizophrenia^1,2. Functional studies have shown that knockdown of Tspan18 leads to reduced endothelial cell migration, invasion and tube formation. Tspan18 has dynamic expression, regulates vascular development and maturation in the embryo with re-expression in adulthood during wound healing³.

Tetraspanins (Tspans) are known as plasma membrane “master organizers.” They form Tspan-enriched microdomains (TEMs or TERMs) through lateral association with one another and other membrane proteins. Tetraspanins are characterized by their four transmembrane domains, made up of two extracellular loops - one small extracellular loop (SEL or EC1) and one larger extracellular loop (LEL or EC2), a short intracellular loop, and two short intracellular tails¹.

Vascular endothelial growth factor (VEGF) signaling is crucial for both vasculogenesis and angiogenesis. VEGF also regulates the Notch pathway and thus arterial–venous specification. Loss of Notch signaling leads to the loss of arterial markers, the gain of venous markers and an increase in vascular sprouting. Tetraspanin 18 (Tspan18) is a novel key regulator of angiogenesis. Tspan18 is one of 33 members of the tetraspanin family. Tetraspanins generate multimolecular complexes resulting in microdomains distinct from lipid rafts. Although tetraspanins typically lack ligands, the tetraspanin microdomains function as signaling complexes in the plasma membrane by interacting with many membrane proteins. Tspan18 is expressed in the blood vessels, and is required for proper angiogenesis, including vessel patterning, vessel stability and arterial–venous specification. Tspan18 signaling also regulates VEGF and Notch pathways and wound healing. Tspan18 deficiency has been shown to reduce VEGF, VEGFR2, Notch3 and EphrinB2, and increase EphB4, VEGFR3, Semaphorin3, Neuropilin and PlexinD1 expression³.

Tspan18 is a novel regulator of thrombo-inflammation, the interplay between thrombosis and inflammation, which causes acute organ damage in diseases such as ischemic stroke and venous thrombosis. The tetraspanin family regulates the trafficking, clustering, and membrane diffusion of specific partner proteins. Tspan18 partners with the store-operated Ca²⁺ entry channel Orai1 on endothelial cells. Orai1 appears to be expressed in all cells and is critical in health and disease. Orai1 mutations cause human immunodeficiency, resulting in chronic and often lethal infections. Orai1 is therefore a promising drug target in autoimmune and inflammatory diseases, and Orai1 inhibitors are currently in clinical trials. Orai1 trafficking to the cell surface is partially impaired in the absence of Tspan18, resulting in impaired Ca²⁺ signaling and the impaired release of the thrombo-inflammatory mediator von Willebrand factor following endothelial stimulation. Consequently, Tspan18-knockout mice are protected in ischemia-reperfusion and deep vein thrombosis models. Tspan18 is relatively highly expressed in endothelial cells, as demonstrated in analysis of publicly available single-cell transcriptomic data. Tspan18 is required for normal Ca²⁺ signaling in platelets, though the functional consequences are subtle and restricted to mildly defective platelet aggregation and spreading induced by the platelet collagen receptor GPVI. Tspan18 also regulates Orai1 Ca²⁺ channel function at the cell surface by promoting its clustering⁴.