Endothelial cells (ECs) line the inside of blood vessels and respond to mechanical cues generated by blood flow. Mechanical stimuli regulate the localization of YAP by reorganizing the actin cytoskeleton. Here we demonstrate blood-flow-mediated regulation of endothelial YAP in vivo. We indirectly monitored transcriptional activity of Yap1 (zebrafish YAP) and its spatiotemporal localization in living zebrafish and found that Yap1 entered the nucleus and promoted transcription in response to blood flow. In cultured human ECs, laminar shear stress induced nuclear import of YAP and its transcriptional activity in a manner independent of Hippo signaling. We uncovered a molecular mechanism by which flow induced the nuclear translocation of YAP through the regulation of filamentous actin and angiomotin. Yap1 mutant zebrafish showed a defect in vascular stability, indicating an essential role for Yap1 in blood vessels. Our data imply that endothelial Yap1 functions in response to flow to maintain blood vessels.

Cadherin-11 (cad-11) is a novel member of the cadherin family of cell adhesion molecules, having recently been identified by means of the polymerase chain reaction. To study the function and expression of this molecule, we cloned mouse, cad-11 cDNA. Transfection of L cells with cDNA led them to acquire a typical cadherin-dependent cell-cell adhesiveness, and the L cells expressing cad-11 did not coaggregate with L cells expressing E-, P-, N-, or R-cadherin when they were mixed, indicating that this novel cadherin has a homophilic binding specificity, as found for other cadherins. To determine the developmental expression pattern of this molecule, we performed in situ hybridization analysis on early mouse embryos. Cad-11 first appeared in mesodermal layers only in the head and tail regions at the mid-to-late primitive streak stages. In the head, this appearance was followed by strong expression in mesenchymal tissues including branchial arches. In the trunk, the paraxial mesoderm initially did not express cad-11. However, as the somites formed, they expressed cad-11, and this expression was strictly correlated with their initial condensation and segregation from the presomitic mesoderm. The cad-11 expression in the somites was eventually restricted to sclerotome cells. As the limb buds developed, cad-11 appeared in the distal portion of the limb mesenchyme, and, at later stages, its expression was most evident at the peripheral mesenchyme. Cad-11 was thus expressed by restricted populations of mesenchymal cells in early embryos, although it was also expressed in parts of the neural tube, such as the optic vesicle and dorsal midline, and in part of the otic vesicle. As a step to investigate the role of cad-11 in mesenchymal cell adhesion, we dissociated the limb bud mesenchyme into single cells, pelleted them, and cultured them as aggregates. In these cultures, cad-11-positive cells clearly sorted out of the negative cell population, suggesting that cad-11 might be involved in selective association of mesenchymal cells. For comparison, we studied the expression of N-cadherin and found that the expressions of these two cadherins were differential, and complementary in some tissues. These results suggest that cad-11 is involved in specific associations of subsets of mesenchymal cells and also of some neural cells during early embryogenesis.

Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance (1H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR “magnetic resonance spectroscopy”). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were 1H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = −0.38; 95% CI, −0.69 to −0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = −0.50; 95% CI, −0.80 to −0.20), but not in unmedicated patients (SMD = −0.27; 95% CI, −0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.

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OSTN might suppress the worsening of CHF after MI by inhibiting clearance of NP family peptides.