Abstract
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.
Highlights
In recent years, mechanistic investigations into brain function and disease have shifted away from a purely ‘‘neurocentric’’ focus into a more integrative perspective that involves all cell types in the central nervous system [1,2,3,4]
Cerebral endothelium may be an important source of signaling and trophic factors that communicate with the brain parenchyma
The brain vasculome may offer a critical tool for investigating how the neurovascular system contributes to the physiology of normal brain function, the pathophysiology of stroke, brain injury and neurodegeneration, as well as provide a database for potential circulating biomarkers that are produced by endothelium in central nervous system (CNS) disorders
Summary
Mechanistic investigations into brain function and disease have shifted away from a purely ‘‘neurocentric’’ focus into a more integrative perspective that involves all cell types in the central nervous system [1,2,3,4]. Signals from astrocytes and pericytes provide important regulatory mechanisms for the blood-brain barrier [6,7,8]. It is recognized that the cerebral endothelium provide a rich source of signaling and trophic factors that influence brain function. Cerebral endothelium can produce growth factors that promote neurogenesis [10]. Oxidatively stressed cerebral endothelium produce lower levels of neurotrophic factors that may lead to increased neuronal susceptibility to stroke and neurodegeneration [15]. Dysfunctional microvessels and disrupted bloodbrain barrier function have been proposed to worsen neuronal dysfunction in Alzheimer’s disease and amyotrophic lateral sclerosis [16,17,18]. Understanding the full functional profile of cerebral endothelium may be extremely important for investigations into CNS physiology and pathophysiology
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