Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation. In mice, endothelial-specific deletion of Yap/Taz led to blunted-end, aneurysm-like tip ECs with fewer and dysmorphic filopodia at the vascular front, a hyper-pruned vascular network, reduced and disarranged distributions of tight and adherens junction proteins, disrupted barrier integrity, subsequent hemorrhage in growing retina and brain vessels, and reduced pathological choroidal neovascularization. Mechanistically, YAP/TAZ activates actin cytoskeleton remodeling, an important component of filopodia formation and junction assembly. Moreover, YAP/TAZ coordinates EC proliferation and metabolic activity by upregulating MYC signaling. Overall, these results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases.

In cancer patients, metastasis of tumors to sentinel lymph nodes (LNs) predicts disease progression and often guides treatment decisions. The mechanisms underlying tumor LN metastasis are poorly understood. By using comparative transcriptomics and metabolomics analyses of primary and LN-metastatic tumors in mice, we found that LN metastasis requires that tumor cells undergo a metabolic shift toward fatty acid oxidation (FAO). Transcriptional coactivator yes-associated protein (YAP) is selectively activated in LN-metastatic tumors, leading to the up-regulation of genes in the FAO signaling pathway. Pharmacological inhibition of FAO or genetic ablation of YAP suppressed LN metastasis in mice. Several bioactive bile acids accumulated to high levels in the metastatic LNs, and these bile acids activated YAP in tumor cells, likely through the nuclear vitamin D receptor. Inhibition of FAO or YAP may merit exploration as a potential therapeutic strategy for mitigating tumor metastasis to LNs.

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BackgroundBioimpedance analysis (BIA) helps measuring the constituents of the body noninvasively. Prior studies suggest that BIA-guided fluid assessment helps to predict survival in dialysis patients. We aimed to evaluate the clinical usefulness of BIA for predicting the survival rate of hemodialysis patients in Korea.MethodsWe conducted a single-center retrospective study. All patients were diagnosed with end-stage renal disorder and started maintenance hemodialysis between June 2009 and April 2014. BIA was performed within the 1st week from the start of hemodialysis. The patients were classified into 2 groups based on volume status measured by the body composition monitor (BCM; Fresenius): an overhydrated group [OG; overhydration/extracellular water (OH/ECW) >15%] and a nonoverhydrated group (NOG; OH/ECW ≤15%).ResultsA total of 344 patients met the inclusion criteria. Of these, 252 patients (73.3%) were categorized into the OG and 92 patients (26.7%) into the NOG. Age- and sex-matching patients were selected with a rate of 2:1. Finally, 160 overhydrated patients and 80 nonoverhydrated patients were analyzed. Initial levels of hemoglobin and serum albumin were significantly lower in the OG. During follow-up, 43 patients from the OG and 7 patients from the NOG died (median follow-up duration, 24.0 months). The multivariate-adjusted all-cause mortality was significantly increased in the OG (odds ratio, 2.569; P = 0.033) and older patients (odds ratio, 1.072/y; P < 0.001). No significant difference of all-cause or disease-specific admission rate was observed between the 2 groups.ConclusionThe ratio of OH/ECW volume measured with body composition monitor is related to the overall survival of end-stage renal disorder patients who started maintenance hemodialysis.

Hypoxia is a main driver of sprouting angiogenesis, but how tip endothelial cells are directed to hypoxic regions remains poorly understood. Here, we show that an endothelial MST1–FOXO1 cascade is essential for directional migration of tip cells towards hypoxic regions. In mice, endothelial‐specific deletion of either MST1 or FOXO1 leads to the loss of tip cell polarity and subsequent impairment of sprouting angiogenesis. Mechanistically, MST1 is activated by reactive oxygen species (ROS) produced in mitochondria in response to hypoxia, and activated MST1 promotes the nuclear import of FOXO1, thus augmenting its transcriptional regulation of polarity and migration‐associated genes. Furthermore, endothelial MST1‐FOXO1 cascade is required for revascularization and neovascularization in the oxygen-induced retinopathy model. Together, the results of our study delineate a crucial coupling between extracellular hypoxia and an intracellular ROS‐MST1‐FOXO1 cascade in establishing endothelial tip cell polarity during sprouting angiogenesis.

Background: Fabry disease (FD) is a recessive X-linked lysosomal storage disorder caused by a-galactosidase A (GLA) deficiency. Although the mechanism is unclear, GLA deficiency causes an accumulation of globotriaosylceramide (Gb3), leading to vasculopathy. Methods: To explore the relationship between the accumulation of Gb3 and vasculopathy, induced pluripotent stem cells generated from four Fabry patients (FD-iPSCs) were differentiated into vascular endothelial cells (VECs). Genome editing using CRISPR-Cas9 system was carried out to correct the GLA mutation or to delete Thrombospondin-1 (TSP-1). Global transcriptomes were compared between wild-type (WT)-and FD-VECs by RNA-sequencing analysis. Findings: Here, we report that overexpression of TSP-1 contributes to the dysfunction of VECs in FD. VECs originating from FD-iPSCs (FD-VECs) showed aberrant angiogenic functionality even upon treatment with recombinant a-galactosidase. Intriguingly, FD-VECs produced more p-SMAD2 and TSP-1 than WT-VECs. We also found elevated TSP-1 in the peritubular capillaries of renal tissues biopsied from FD patients. Inhibition of SMAD2 signaling or knock out of TSP-1 (TSP-1 À/À ) rescues normal vascular functionality in FD-VECs, like in gene-corrected FD-VECs. In addition, the enhanced oxygen consumption rate is reduced in TSP-1 À/À FD-VECs. Interpretation: The overexpression of TSP-1 secondary to Gb3 accumulation is primarily responsible for the observed FD-VEC dysfunction. Our findings implicate dysfunctional VEC angiogenesis in the peritubular capillaries in some of the complications of Fabry disease.

Initial serum GDF 15 level showed an inverse correlation with serum eGFR and was associated with worse renal outcome. Our results suggested that GDF 15 may play a role as a potential prognosticator in IgAN.

Membranous nephropathy (MGN) is the most common cause of the nephrotic syndrome in adults. Most cases of MGN are primary, but secondary MGN are frequently encountered. Determination of secondary MGN is crucial for initiation of appropriate treatment. The diagnostic performance of the phospholipase A2 receptor (PLA2R) and immunoglobulin G4 (IgG4) detection based on immunohistochemistry were evaluated using biopsy tissues of 59 primary and 56 secondary MGN cases for discrimination between primary MGN and secondary MGN. The PLA2R and IgG4 detection based on immunohistochemistry were dominantly positive in primary MGN cases. Sensitivity and specificity values for identification of primary MGN were 83% and 88% for PLA2R, and 76% and 86% for IgG4. Both PLA2R and IgG4 positivity showed a high specificity of 96.4% for identifying primary MGN. A meta-analysis was performed for analysis of the diagnostic accuracy of histologic PLA2R and IgG4 deposition for differentiation of primary from secondary MGN. The overall sensitivity, specificity, and area under curve of summary receiver operating characteristics were 76%, 86%, 0.93 for histologic PLA2R deposition, and 80%, 69%, 0.82 for histologic IgG4 deposition. PLA2R and IgG4 detection based on immunohistochemistry can be useful for differentiation of primary MGN from secondary MGN.