The Vasculome of the Mouse Brain

The blood vessel is no longer viewed as passive plumbing for the brain. Increasingly, experimental and clinical findings suggest that cerebral endothelium may possess endocrine and paracrine properties – actively releasing signals into and receiving signals from the neuronal parenchyma. Hence, metabolically perturbed microvessels may contribute to central nervous system (CNS) injury and disease. Furthermore, cerebral endothelium can serve as sensors and integrators of CNS dysfunction, releasing measurable biomarkers into the circulating bloodstream. Here, we define and analyze the concept of a brain vasculome, i.e. a database of gene expression patterns in cerebral endothelium that can be linked to other databases and systems of CNS mediators and markers. Endothelial cells were purified from mouse brain, heart and kidney glomeruli. Total RNA were extracted and profiled on Affymetrix mouse 430 2.0 micro-arrays. Gene expression analysis confirmed that these brain, heart and glomerular preparations were not contaminated by brain cells (astrocytes, oligodendrocytes, or neurons), cardiomyocytes or kidney tubular cells respectively. Comparison of the vasculome between brain, heart and kidney glomeruli showed that endothelial gene expression patterns were highly organ-dependent. Analysis of the brain vasculome demonstrated that many functionally active networks were present, including cell adhesion, transporter activity, plasma membrane, leukocyte transmigration, Wnt signaling pathways and angiogenesis. Analysis of representative genome-wide-association-studies showed that genes linked with Alzheimer’s disease, Parkinson’s disease and stroke were detected in the brain vasculome. Finally, comparison of our mouse brain vasculome with representative plasma protein databases demonstrated significant overlap, suggesting that the vasculome may be an important source of circulating signals in blood. Perturbations in cerebral endothelial function may profoundly affect CNS homeostasis. Mapping and dissecting the vasculome of the brain in health and disease may provide a novel database for investigating disease mechanisms, assessing therapeutic targets and exploring new biomarkers for the CNS

Mortality of emergency abdominal surgery in high-, middle- and low-income countries

Background: Surgical mortality data are collected routinely in high-income countries, yet virtually no low- or middle-income countries have outcome surveillance in place. The aim was prospectively to collect worldwide mortality data following emergency abdominal surgery, comparing findings across countries with a low, middle or high Human Development Index (HDI). Methods: This was a prospective, multicentre, cohort study. Self-selected hospitals performing emergency surgery submitted prespecified data for consecutive patients from at least one 2-week interval during July to December 2014. Postoperative mortality was analysed by hierarchical multivariable logistic regression. Results: Data were obtained for 10 745 patients from 357 centres in 58 countries; 6538 were from high-, 2889 from middle- and 1318 from low-HDI settings. The overall mortality rate was 1⋅6 per cent at 24 h (high 1⋅1 per cent, middle 1⋅9 per cent, low 3⋅4 per cent; P < 0⋅001), increasing to 5⋅4 per cent by 30 days (high 4⋅5 per cent, middle 6⋅0 per cent, low 8⋅6 per cent; P < 0⋅001). Of the 578 patients who died, 404 (69⋅9 per cent) did so between 24 h and 30 days following surgery (high 74⋅2 per cent, middle 68⋅8 per cent, low 60⋅5 per cent). After adjustment, 30-day mortality remained higher in middle-income (odds ratio (OR) 2⋅78, 95 per cent c.i. 1⋅84 to 4⋅20) and low-income (OR 2⋅97, 1⋅84 to 4⋅81) countries. Surgical safety checklist use was less frequent in low- and middle-income countries, but when used was associated with reduced mortality at 30 days. Conclusion: Mortality is three times higher in low- compared with high-HDI countries even when adjusted for prognostic factors. Patient safety factors may have an important role. Registration number: NCT02179112 (http://www.clinicaltrials.gov)

The vasculome of mouse brain is unique and different from those found in mouse heart and kidney.

<p>Heatmap for visualization of the expression levels of organ-specific endothelial genes across brain, heart and kidney glomeruli. X-axis represents individual samples and y-axis represents different genes. The expression levels of genes are indexed by color.</p

Angiogenesis networks.

<p><b>A</b>, Protein-protein interaction network for angiogenesis in the vasculome of mouse brain (including nearest neighbors). Circles for genes in angiogenesis and squares for the neighbor genes. The expression levels of genes in the vasculome of mouse brain are indexed by color. <b>B</b>, Heatmap comparison of expression profiles of genes in the VEGF signaling pathway from the vasculome of mouse brain, heart and kidney glomeruli. The expression levels of genes are indexed by color.</p

Enriched pathways detected in the vasculome of mouse brain.

<p>Note: Analysis based on brain endothelial specific genes in the mouse brain vasculome. These enriched pathways suggest that specific pathways and mechanisms are selectively enhanced in brain compared to heart and kidney glomerular vasculomes.</p

Protein-protein interaction (PPI) networks in the vasculome of mouse brain.

<p><b>A,</b> PPI network for leukocyte transendothelial migration. <b>B,</b> PPI network for the WNT signaling pathway. <b>C,</b> PPI network for adherence junctions. The expression levels of genes in the vasculome of mouse brain are indexed by color.</p

Expression of disease-related genes in the vasculome of mouse brain.

<p>Expression of disease-related genes in the vasculome of mouse brain.</p

Expression of plasma proteins in the vasculome of mouse brain.

<p>Note: *core is the intersect of all 4 independent data set. Lists of circulating proteins in human plasma were compiled from 4 different proteomic studies, then each study was overlapped with the expression profile of the brain vasculome. A core set of 387 proteins were defined as common proteins detected in all 4 human plasma protein studies. Out of the core set of plasma proteins, 100 proteins were expressed in the brain vasculome.</p