LAUSR

Endostatin was originally isolated from murine hemangioendothelioma culture medium that inhibited tumor angiogenesis and growth, and biochemical analysis revealed it to be a C-terminal fragment of collagen XVIII. Collagen XVIII is a non-fibrillar collagen ubiquitously expressed and accumulated in basement membrane (BM) throughout the body. There are three isoforms of collagen XVIII: long, middle, and short. These isoforms differ in their N-terminal non-collagenous 2 domain but share collagenous and C-terminal non-collagenous 1 (NC1) domain containing endostatin. These three isoforms of collagen XVIII are encoded by a single COL18A1 gene on chromosome 21q22.3, but the expression and localization of the gene products are different. For example, the long isoform of collagen XVIII is found selectively in the liver, whereas the short isoform is present in various epithelial and endothelial BM. BM is degraded proteolytically during its turnover, and that generates matricryptins including endostatin. Matricryptins are bioactive fragments originated by the proteolytic cleavage of extracellular matrices. For the generation of endostatin, various proteases such as matrix metalloproteinases, elastase, and cathepsins cleave the hinge region of the NC1 domain of collagen XVIII and release a 20-kDa endostatin as well as endostatin-containing fragments with molecular weights varying from 24 to 28 kDa. Because of the distinctive role of endostatin in tumor angiogenesis and growth, ELISA for endostatin was soon developed and its level was tested for the application as a biomarker. Previous studies focused on various cancers, but later on, other pathological conditions such as bronchopulmonary dysplasia, pulmonary arterial hypertension, traumatic brain injury, Alzheimer’s disease, peripheral vascular disease, and chronic kidney disease were included. In this issue of the journal, Kato et al. examined serum endostatin concentration in Japanese healthy population and revealed for the first time that a higher serum endostatin concentration reflects the presence of subclinical carotid atherosclerosis. The relationship between endostatin and atherosclerosis is reported as follows: the administration of endostatin inhibited adventitial angiogenesis and intimal plaque formation in apoE mice, whereas the absence of col18a1 gene exacerbated atherosclerosis in apoE mice. Patients with Down syndrome (trisomy 21) had elevated serum endostatin concentration and had a reduced prevalence of atherosclerosis. Accordingly, because of the property of angiogenesis inhibitor, endostatin is anti-atherosclerotic. Therefore, the elevated serum endostatin concentration in this Japanese healthy population should not be the cause of carotid atherosclerosis but the result of basement membrane degradation probably from the vasculature during the development of atherosclerosis. Seemingly, although the elevated serum endostatin concentration is not specific to atherosclerosis, it can be a possible surrogate marker that suggests the presence of subclinical carotid atherosclerosis with basement membrane degradation.