Angiotensin-converting enzyme and chymase, two Ang II-forming enzymes, are locally expressed in aortic valves, and owing to infiltration of macrophages and MCs, are further upregulated in stenotic valves. These novel findings, implicating chronic inflammation and an increased expression of local Ang II-forming systems, suggest that therapeutic interventions aiming at inhibiting these processes may slow AS progression.

Extensive angiogenesis and invasion of the maternal decidua by trophoblasts are essential for the development and function of the placenta. Vascular endothelial growth factors (VEGF), placenta growth factor (PlGF) and their receptors VEGFR-1/Flt-1, VEGFR-2/KDR and VEGFR-3/Flt4 have important roles in vasculogenesis and angiogenesis. We have studied the localization of these proteins by immunohistochemistry and Western blotting in the placenta and of PlGF in maternal serum, and their association with diabetes, pre-eclampsia, fetal growth restriction (FGR) and fetal alcohol syndrome (FAS). VEGFR-1 and VEGFR-3 were detected mainly in the syncytiotrophoblastic layer whereas VEGFR-2 was detected in the vascular endothelial cells of the placenta. VEGFR-1, but not the other receptors, showed increased expression in placental syncytiotrophoblasts from 50% of patients with severe pre-eclampsia and FGR when compared with normal placentas. PlGF was undetectable in 38 of 44 samples of amniotic fluid of mothers with normal and complicated pregnancies. However, maternal serum PlGF concentrations were significantly lower in pre-eclamptic patients and in those with FGR when compared to diabetic women or healthy controls. These results suggest that low maternal serum PlGF and increased placental expression of its receptor VEGFR-1 are associated with pre-eclampsia and FGR.

In stenotic aortic valves, mast cell-derived cathepsin G may cause adverse valve remodelling and AS progression.

Recent findings regarding the interaction of inflammatory cells, lipids, mediators of calcification, and renin-angiotensin system in stenotic valves support the current opinion of aortic valve stenosis being an actively regulated disease, potentially amenable to targeted molecular therapy. Evidence from prospective clinical studies is eagerly awaited.

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Objective-To investigate the possible role of elastolytic cathepsins S, K, and V and their endogenous inhibitor cystatin C in adverse extracellular matrix remodeling of stenotic aortic valves. Methods and Results-Stenotic aortic valves were collected at valve replacement surgery and control valves at cardiac transplantations. The expression of cathepsins S, K, and V and cystatin C was studied by conventional and real-time polymerase chain reaction and by immunohistochemistry. Total cathepsin activity in the aortic valves was quantified by a fluorometric microassay. When compared with control valves, stenotic valves showed increased mRNA expression of cathepsins S, K, and V (PϽ0.05 for each) and a higher total cathepsin activity (PϽ0.001). In stenotic valves, cystatin C mRNA was increased (PϽ0.05), and cystatin C protein was found particularly in areas with infiltrates of inflammatory cells. Both cathepsin S and cystatin C were present in bony areas of the valves, whereas cathepsin V localized to endothelial cells in areas rich of neovascularization. Incubation of thin sections of aortic valves with cathepsins S, K, and V resulted in severe disruption of elastin fibers, and this cathepsin effect could be blocked by adding cystatin C to the incubation system. Key Words: aortic stenosis Ⅲ cathepsin Ⅲ cystatin C Ⅲ elastin Ⅲ heart valves A ortic stenosis is an active inflammatory process resembling atherosclerosis. The pathophysiological changes in the stenotic aortic valves include inflammatory cell infiltration, neoangiogenesis, accumulation of lipids, and active mediators of calcification with extracellular matrix (ECM) degradation. 1-7 Furthermore, aortic valvular myofibroblasts undergo phenotypic changes toward an osteoblast-like phenotype, and active bone formation and remodeling occur in the stenotic valves. 8,9 These processes lead to loss of normal valvular geometry, disruption of the elastic fibers, and accumulation of fibrocalcific masses. This adverse remodeling of the valves is associated with the loss of their mechanical and elastic properties, leading to thickening and stiffening of the valve leaflets and to progression of aortic stenosis. Conclusions-StenoticThe pathophysiological mechanisms involved in the abnormal accumulation and degradation of ECM in the valves are incompletely understood. In atherosclerotic lesions, elastolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage, whereas their endogenous inhibitor, cystatin C, is severely reduced. 10,11 Moreover, a marked deficiency of cystatin C expression with accentuated cathepsin S and K expression in aortic aneurysms and a negative correlation of cystatin C serum levels with the diameter of abdominal aorta has been reported. 11 These observations support the role of an imbalance between cathepsins and cystatin C in diseases characterized by pathological elastin degradation. In addition, cathepsin K has a crucial role in bone matrix degradation necessary for normal bone growth and remodeling...

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