The avascularity of cardiac valves is abrogated in several valvular heart diseases. This study investigated the molecular mechanisms underlying valvular avascularity, and its correlation with valvular heart diseases induction. Chondromodulin-I, an anti-angiogenic factor isolated from the cartilage, is abundantly expressed in normal murine, rat and human cardiac valves. It is first detected at developmental stage E9.5 in the left ventricle, outflow tract and valvular primordium, but is restricted to cardiac valves from late embryogenesis to the adult. Gene targeting of chondromodulin-1 resulted in enhanced VEGF-A expression, angiogenesis, lipid deposition and calcification in the cardiac valves of aged mice. Echocardiography revealed aortic valve thickening, calcification and turbulent flow signifying early changes in aortic stenosis. Conditioned medium obtained from cultured valvular interstitial cells strongly inhibited tube formation, mobilized endothelial cells and induced their apoptosis, and these effects were partially inhibited by chondromodulin-1 siRNA. In both ApoE–/– mice and human valvular heart diseases, including infective endocarditis, rheumatic heart disease and atherosclerosis, VEGF-A expression, neovascularization and calcification were observed in the areas of chondromodulin-1 down-regulation. These findings provide evidence that chondromodulin-I plays a pivotal role in maintaining valvular normal function by preventing angiogenesis, thickening and calcification that may lead to valvular heart diseases. [J Physiol Sci. 2007;57 Suppl:S7]
