To address the requirement for TGFbeta signaling in the formation and maintenance of the vascular matrix, we employed lineage-specific mutation of the type II TGFbeta receptor gene (Tgfbr2) in vascular smooth muscle precursors in mice. In both neural crest- and mesoderm-derived smooth muscle, absence of TGFbeta receptor function resulted in a poorly organized vascular elastic matrix in late-stage embryos which was prone to dilation and aneurysm. This defect represents a failure to initiate formation of the elastic matrix, rather than a failure to maintain a preexisting matrix. In mutant tissue, lysyl oxidase expression was substantially reduced, which may contribute to the observed pathology.

The employment of a multidentate salicylamide salen-like ligand, 2-hydroxy-N-(2-(2-hydroxybenzylidene)amino)ethyl)benzamide (H3L), in aid of NO3(-) anions under weak basic conditions in Zn(II)-Ln(III) chemistry (Ln = Eu, and Dy, ) led to the isolation of two novel butterfly heterometallic dodecanuclear clusters with six Ln(III) ions occupying the body position and six Zn(II) ions the outer wing-tip sites. All of them are fully characterized by elemental analysis, FT-IR spectroscopy, TG analysis, single-crystal X-ray diffraction, and X-ray powder diffraction (XRPD) techniques. Luminescence studies indicate that exhibits dual emission, while exhibits a bright blue emission under visible light excitation. Furthermore, magnetic susceptibility studies carried out for indicate that the magnetic exchange between Dy(III) ions revealed ferromagnetic interactions with interesting slow relaxation of magnetization of the SMM behavior.

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Objective Calcific aortic valve disease is a significant clinical problem for which the regulatory mechanisms are poorly understood. Enhanced cell-cell adhesion is a common mechanism of cellular aggregation, but its role in calcific lesion formation is not known. Cadherin-11 (Cad-11) has been associated with lesion formation in vitro, but its function during adult valve homeostasis and pathogenesis is not known. This study aims to elucidate the specific functions of Cad-11 and its downstream targets RhoA and Sox9 in extracellular matrix remodeling and aortic valve calcification. Approach and Results We conditionally overexpressed Cad-11 in murine heart valves using a novel double transgenic Nfatc1Cre;R26-Cad11Tg/Tg mouse model. These mice developed hemodynamically significant aortic stenosis with prominent calcific lesions in the aortic valve leaflets. Cad-11 overexpression upregulated downstream targets RhoA and Sox9 in the valve interstitial cells, causing calcification and extensive pathogenic extracellular matrix remodeling. Aortic valve interstitial cells overexpressing Cad-11 in an osteogenic environment in vitro rapidly form calcific nodules analogous to in vivo lesions. Molecular analyses revealed upregulation of osteoblastic and myofibroblastic markers. Treatment with a ROCK inhibitor attenuated nodule formation, further supporting that Cad-11 driven calcification acts through the small GTPase RhoA/ROCK signaling pathway. Conclusions This study identifies one of the underlying molecular mechanisms of heart valve calcification and demonstrates that overexpression of Cad-11 upregulates RhoA and Sox9 to induce calcification and extracellular matrix remodeling in adult aortic valve pathogenesis. The findings provide a potential molecular target for clinical treatment.

Proper remodeling of the endocardial cushions into thin fibrous valves is essential for gestational progression and long-term function. This process involves dynamic interactions between resident cells and their local environment, much of which is not understood. In this study, we show that deficiency of the cell-cell adhesion protein cadherin-11 (cad-11) results in significant embryonic and perinatal lethality primarily due to valve related cardiac dysfunction. While endocardial to mesenchymal transformation is not abrogated, mesenchymal cells do not homogeneously cellularize the cushions. These cushions remain thickened with disorganized ECM, resulting in pronounced aortic valve insufficiency. Mice that survive to adulthood maintain thickened and stenotic semilunar valves, but interestingly do not develop calcification. Cad-11 −/− aortic valve leaflets contained reduced sox9 activity, β1 integrin expression, and RhoA-GTP activity, suggesting that remodeling defects are due to improper migration and/or cellular contraction. Cad-11 deletion or siRNA knockdown reduced migration, eliminated collective migration, and impaired 3D matrix compaction by aortic valve interstitial cells (VIC). Cad-11 depleted cells in culture contained few filopodia, stress fibers, or contact inhibited locomotion. Transfection of Cad-11 depleted cells with constitutively active RhoA restored cell phenotypes. Together, these results identify cadherin-11 mediated adhesive signaling for proper remodeling of the embryonic semilunar valves.