The Vasculome of the Mouse Brain

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.

Vasculogenesis in Experimental Stroke After Human Cerebral Endothelial Cell Transplantation

“…The detection of microvascular morphology in HEN6-grafted stroke animals might have been similarly achieved in the in vitro condition, although likely masked by the short period and incomplete neurovascular unit in the cell culture system. The host microenvironment, in particular the notion of a vasculome in the brain, 39 may also contribute to the fate and function of transplanted cells. These speculative secretory and cell substrate mechanisms warrant further investigations.…”

Mechanisms of Neurovascular Dysfunction in Acute Ischemic Brain

“…Thus far, endothelial-derived MPs (EMPs) have been prominently researched. EMPs are highly organ-dependent [111], and are suggested as markers of endothelial dysfunction [112]. Production of EMPs is known to be stimulated by mediators such as TNF-α [113], thereafter increased EMPs convey proteases of matrix metalloproteinase family or mRNA that may promote recovery via angiogenesis under certain circumstances [114, 115].…”

Glutamate Efflux at the Blood–Brain Barrier: Cellular Mechanisms and Potential Clinical Relevance

“…Brain capillaries from mice have been shown to have a high expression of EAAT-3 mRNA (22,37,38) as well as protein expression of EAAT-1, -2 and -3 (although mainly subtypes -1 and -2) (39). Freshly isolated bovine brain capillaries express EAAT-1, -2 and -3 mRNA, whereas only EAAT-1 has been detected at the protein level (21,40).…”