Serum Tenascin-X Strongly Binds to Vascular Endothelial Growth Factor

Abstract

The extracellular matrix (ECM) was originally thought to be merely a physical framework for cells in terms of mechanical strength. However, this concept has been revised in recent years. The ECM is now known to participate in cell proliferation, migration, differentiation, and survival.1) The ECM contains not only many adhesive proteins, including fibronectin, collagen and laminin, which generally promote cell attachment or migration, but also adhesive modulatory proteins such as tenascin, thrombospondin and SPARC/ osteonectin/BM40, which regulate the interactions between cell receptors and adhesive proteins.Among adhesive modulatory proteins, the tenascin family constitutes a group of ECM glycoproteins with a characteristic structure. The four members of this family identified so far [tenascin-C (TNC), restrictin/J1-160/180 (tenascin-R, TNR), tenascin-X (TNX), and tenascin-W/tenascin-N (TNW/TNN)] have been found in vertebrates.2-6) Tenascin family members are made up of the same types of structural domains, including a cysteine-rich segment at the amino terminus, epidermal growth factor (EGF)-like repeats, fibronectin type III (FNIII)-like repeats, and a fibrinogen-like domain at the carboxyl terminus.TNX is the largest member of the tenascin family. Complete deficiency of TNX in humans leads to a rare recessive form of Ehlers-Danlos Syndrome (EDS), and TNX haploinsufficiency is associated with hypermobility type of EDS. The skin of TNX-deficient patients is markedly lax with poor recoil properties and shows easy bruising. [7][8][9] In the skin of these patients, the collagen density is reduced in the dermis, and the elastic fibers are abnormal. Furthermore, recent genetic studies have revealed a strong association between the TNX locus and other diseases such as schizophrenia, 10) arterial tortuosity syndrome (ATS), 11) and systemic lupus erythematosus.12) Recent evidence has suggested that TNX is involved in collagen fibrillogenesis, 13,14) collagen deposition, 15) and development and maintenance of elastic fibers. 16) As a biological feature of TNX, it has been shown that TNX interacts with types I, III and V fibrillar collagen and fibril-associated types XII and XIV collagen 15,17) and with proteoglycan decorin. 18)Schalkwijk et al. 8) reported that human TNX is also present in normal serum with an apparent molecular size of 140 kDa. Measurement of serum TNX revealed that high levels of serum TNX are a risk factor for abdominal aortic aneurysm. 19) We previously identified the serum form of TNX (referred to as sTNX) with a molecular mass of 200 kDa in the mouse, 20) and we gave the name iTNX to conventional interstitial TNX. The full-length iTNX has a molecular mass of about 450 kDa. The 200-kDa sTNX contains the last 15 FNIII repeats and a fibrinogen domain identical to the C-terminal portion of the 450-kDa iTNX. The N-terminus of sTNX is located in the juncture between the 16th FNIII and 17th FNIII repeats. Furthermore, 200-kDa sTNX is generated by proteolytic cleavage of the 450-kDa iTNX.A number of frag...

Tenascin-X Induces Cell Detachment through p38 Mitogen-Activated Protein Kinase Activation

“…24,25) As negative controls, the wells were coated with the same amount of extract [referred to as Ctrl(TNXϪ/Ϫ)] purified from TNX-deficient (TNXϪ/Ϫ) mice 26) or with phosphate-buffered saline (PBS) [referred to as Ctrl(PBS)]. Ctrl(TNXϪ/Ϫ) was extracted from livers of TNXϪ/Ϫ mice by the same procedures as TNX from wildtype mice had been purified.…”

“…24,25) Then we investigated adhesive properties of the purified TNX to mouse fibroblast L cells (Fig. 1A).…”

Increased Expression of Tenascin-X in Thoracic and Abdominal Aortic Aneurysm Tissues

“…Since we previously demonstrated that TNX in combination with VEGF family members enhances endothelial cell proliferation, 18,19) we thought it would be interesting to know whether TNX expression is associated with expression of VEGF-A in TAA and AAA tissues, in which the level of TNX is increased. As expected, VEGF-A level was significantly increased in TAA tissues (pϭ0.022), in coincidence with the increased expression of TNX, but not in AAA tissues.…”

“…14) Furthermore, TNX binds to VEGF family members, leading to an enhancement of endothelial cell proliferation. 18,19) Therefore, we investigated the expression level of VEGF-A in each TAA tissue and each AAA tissue (lane A) compared with that in adjacent normal aorta tissues (lane N), as shown in Figs. 1Ac (patient #7), 1Ad (patient #14), 1Bc, 1Bd, 1Cc, and 1Cd.…”

“…18) Serum TNX also binds to VEGF-A and VEGF-B and possesses weak activity for proliferation of endothelial cells. 19) TNC has been observed in the stroma around blood vessels that are undergoing angiogenesis in AAAs. 14) These findings suggest that the tenascin family plays important roles in the neovascularization of aortic wall in abdominal and thoracic aortic aneurysms.…”