Preparation and evaluation of 111In-labeled liposomes containing phosphatidylglycerol for detection of macrophages in atherosclerotic plaques.

Macrophage infiltration is a characteristic feature of atherosclerotic plaque progression. Since liposomes containing 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) are efficiently phagocytosed by macrophages, we deduced that radiolabeled liposomes containing DSPG could potentially be used for nuclear imaging of vulnerable atherosclerotic plaques. Indium-111 (111In)-labeled liposomes containing different ratios of DSPG were developed with a high labeling efficiency. 111In-labeled liposomes with higher DSPG content showed higher uptake by macrophage-like RAW264 cells. A biodistribution study demonstrated rapid blood clearance and selective accumulation in the liver and spleen, especially in normal mice injected with 111In-labeled liposomes with higher DSPG content. Accumulation in atherosclerotic plaques was evaluated using 111In-labeled DSPG liposomes, which had the highest DSPG content among the studied liposomes. 111In-labeled DSPG liposomes accumulated in the plaques and the radioactive regions were mostly consistent with the distribution of macrophages. The target-to-non-target ratio of 111In-labeled DSPG liposomes was higher than that of 111In-labeled control liposomes without DSPG. These results suggest that 111In-labeled liposomes containing DSPG are useful for nuclear medical diagnosis of atherosclerotic plaques.

Involvement of endothelial nitric oxide in sphingosine-1-phosphate-induced angiogenesis.

Nitric oxide (NO) has been implicated as a critical signaling molecule of angiogenesis. Recently, sphingosine-1-phosphate (S1P) has emerged as a mediator of angiogenesis, and S1P-induced NO synthesis in endothelial cells (ECs) has been reported. To analyze the signaling pathways involved in S1P-induced angiogenesis and clarify the role of NO in this process, we performed in vivo and in vitro angiogenesis assays. S1P activated the phosphatidylinositol-3-kinase (PI3K)/Akt/endothelial NO synthase (eNOS) pathway in ECs, since S1P-stimulated eNOS phosphorylation and NO production were blocked by inhibition of activities of PI3K and Akt. S1P increased capillary ingrowth into subcutaneously implanted Matrigel plugs in mice, and the effect of S1P was significantly reduced in mice that received N(G)-nitro- L-arginine methyl ester (L-NAME), an inhibitor of NOS. S1P stimulated EC migration and tube formation on Matrigel, which processes were significantly decreased by inhibition of activities of PI3K, Akt, or eNOS, whereas treatment with LY294002, a PI3K inhibitor, but not L-NAME, inhibited EC viability and proliferation. Thus, our results demonstrate the crucial role of NO in S1P-induced angiogenesis in vivo and in vitro and suggest the divergent roles of NO in the S1P-induced angiogenic response.

Nectins and nectin-like molecules in development and disease.

Nectins and nectin-like molecules (Necls)/Cadms are Ca(2+)-independent immunoglobulin superfamily cell adhesion molecules, expressed in most cell types. Nectins mediate not only homotypic but also heterotypic cell-cell adhesion, in contrast to classic cadherins which participate only in homophilic adhesion. Nectins and Necls function in organogenesis of the eye, inner ear, tooth, and cerebral cortex and in a variety of developmental processes including spermatogenesis, axon guidance, synapse formation, and myelination. They are also involved in various diseases, such as viral infection, hereditary ectodermal dysplasia, Alzheimer's disease, autism spectrum disorder, and cancer. Thus, nectins and Necls are crucial for both physiology and pathology. This review summarizes recent advances in research on these cell adhesion molecules in development and pathogenesis.