Septation of the mammalian heart into four chambers requires the orchestration of multiple tissue progenitors. Abnormalities in this process can result in potentially fatal atrioventricular septation defects (AVSD). The contribution of extracardiac cells to atrial septation has recently been recognized. Here, we use a genetic marker and novel magnetic resonance microscopy techniques to demonstrate the origins of the dorsal mesenchymal protrusion in the dorsal mesocardium, and its substantial contribution to atrioventricular septation. We explore the functional significance of this tissue to atrioventricular septation through study of the previously uncharacterized AVSD phenotype of Shh -/-mutant mouse embryos. We demonstrate that Shh signaling is required within the dorsal mesocardium for its contribution to the atria. Failure of this addition results in severe AVSD. These studies demonstrate that AVSD can result from a primary defect in dorsal mesocardium, providing a new paradigm for the understanding of human AVSD.
P-selectin expression is involved in the pathophysiology of biologically active arterial thrombus and endothelial activation after a transient ischemic event. Fucoidan is a polysaccharidic ligand of P-selectin, with a nanomolar affinity. In the present study, we propose a new approach of P-selectin molecular imaging based on radiolabeled fucoidan. Methods: Two kinds of experimental models were selected to evaluate the ability of radiolabeled fucoidan to detect P-selectin expression: plateletrich arterial thrombi (vegetations of infective endocarditis and arterial mural thrombus) and myocardial ischemia-reperfusion. These 2 settings were chosen because they were clinically relevant, and both were associated with an important overexpression of platelet and endothelial P-selectin, respectively. Results: 99m Tc-fucoidan SPECT was able to detect the presence of platelet-rich arterial thrombi in all animals, with a median target-to-background ratio of 5.2 in vegetations of endocarditis and 3.6 in mural aneurysmal thrombus, and to detect a persistent endothelial activation at 2 h after reperfusion. In this latter model, the magnitude of the signal was correlated with the extent of myocardium that underwent transient ischemia. The sensitivity of selectivity of the uptake and retention of 99m Tc-fucoidan in both settings was excellent. Conclusion: This study supports 99m Tc-fucoidan as a relevant imaging agent for in vivo detection of biologic activities associated with P-selectin overexpression, such as arterial thrombus and ischemic memory. Given the reported wide availability at a low cost, and its low toxicity, fucoidan seems to overcome some of the limitations of previous P-selectin-targeted imaging agents.Key Words: P-selectin; fucoidan; thrombus; ischemia; imaging J Nucl Med 2011; 52:1433-1440 DOI: 10.2967/jnumed.110.085852 P-sel ectin is an adhesion molecule expressed at the surface of endothelial cells and platelets on activation. It mediates leukocyte rolling on activated endothelium (1) and leukocyte trapping on platelet aggregates (2), through the interaction with its counterreceptor P-selectin glycoprotein ligand 1. In the cardiovascular field, P-selectin expression is involved in the pathophysiology of 2 settings of prominent clinical relevance: the renewal and growth of biologically active (at risk) arterial thrombus (2) and endothelial activation after an acute transient myocardial ischemic event referred to as ischemic memory (3). Activated platelets expose granular P-selectin on their membrane surface, and myocardial injury is associated with activation of endothelial cells resulting in Weibel-Palade bodies exocytosis and overexpression of adhesion molecules (1,4), which persists after ischemia has resolved. Therefore, P-selectin promotes platelet, endothelium, and leukocyte interactions, whatever the cardiovascular events, representing an important molecular target in acute and in chronic cardiovascular diseases.Consequently, many efforts have been made to develop imaging agents targeting P-selectin (5...
Engineered mice play an ever-increasing role in defining connections between genotype and phenotypic expression. The potential of magnetic resonance microscopy (MRM) for morphologic phenotyping in the mouse has previously been demonstrated; however, applications have been limited by long scan times, availability of the technology, and a foundation of normative data. This article describes an integrated environment for high-resolution study of normal, transgenic, and mutant mouse models at embryonic and neonatal stages. Three-dimensional images are shown at an isotropic resolution of 19.5 m (voxel volumes of 8 pL), acquired in 3 h at embryonic days 10.5-19.5 (10 stages) and postnatal days 0 -32 (6 stages). A web-accessible atlas encompassing this data was developed, and for critical stages of embryonic development (prenatal days 14.5-18.5), >200 anatomical structures have been identified and labeled. Also, matching optical histology and analysis tools are provided to compare multiple specimens at multiple developmental stages. The utility of the approach is demonstrated in characterizing cardiac septal defects in conditional mutant embryos lacking the Smoothened receptor gene. Finally, a collaborative paradigm is presented that allows sharing of data across the scientific community. This work makes magnetic resonance microscopy of the mouse embryo and neonate broadly available with carefully annotated normative data and an extensive environment for collaborations. digital atlas ͉ magnetic resonance microscopy ͉ mouse embryo
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