Cerebral microvessel endothelial cells

Since the first attempts in the 1970s to isolate cerebral microvessel endothelial cells (CECs) in order to model the BBB in vitro, the need for a human BBB model that closely mimics the in vivo phenotype and is reproducible and easy to grow has been widely recognized by cerebrovascular researchers in both academia and industry [22]. While primary human CECs would ideally be the model of choice, the paucity of available fresh human cerebral tissue makes wide-scale studies impractical. The brain microvascular endothelial cell line hCMEC/D3 represents one such model of the human BBB that can be easily grown and is amenable to cellular... 

Guillot, F.L. and Audus, K.L. (1990) Angiotensin peptide regulation of fluid-phase endocytosis in brain microvessel endothelial cell monolayers. Journal of Cerebral Blood Flow and Metabolism, 10, 827-834,... 

El-Bacha RS, Minn A. Drug metabolizing enzymes in cerebrovascular endothelial cells afford a metabolic protection to the brain. Cell Mol Biol 1999 45 15-23 Minn A, Ghersi-Egea JF, Perrin R, Leininger B, Siest G. Drug metabolizing enzymes in the brain and cerebral microvessels. Brain Res Rew 1991 16 65-82. 

A2B receptors are found on endothelial cells, where they regulate vascular permeability, and on epithelial cells, where they regulate water secretion. These receptors are upregulated in the hippocampus following cerebral ischemic preconditioning and are thought to play a protective role. Both A2A and A2B receptors contribute to dilation of cerebral microvessels in response to adenosine. 

The cerebral endothelial cells of the blood-brain barrier originate from the middle germinal sheet of the embryo, the mesoderm [17]. Concomitant with migration and proliferation of capillary endothelial cells during formation of the cerebral vascular network occurs the imprinting of the cells. Thereby, induction by the cellular surrounding plays an important role [18-21], The relevance of the cellular environment for the development of the barrier function of cerebral microvessels was first demonstrated by Stewart and Wiley [22], who transplanted embryonic brain tissue of a quail into embryonic gut tissue of chicken and vice versa. The cerebral transplant was vascularized by intestinal vessels, in which properties of the blood-brain barrier had been induced. In transplanted brain vessels, however, no characteristics of a barrier could be demonstrated, due to the lack of a neuronal environment. These results indicated that the cerebral microvessels are of extraneuronal origin, with properties that are induced by the cellular environment. In addition, brain tissue has the capability to induce blood-brain barrier characteristics also in noncerebral vascular tissue [23],... 

The blood-brain barrier is a biochemical as well as a physical barrier. Brain endothelial cells create an enzymatic barrier composed of secreted proteases and nucleotidases, as well as intracellular metabolizing enzymes such as cytochrome P-450. Furthermore, y-glutamyl transpeptidase, alkaline phosphatase, and aromatic acid decarboxylase are more prevalent in cerebral microvessels than in nonneuronal capillaries. The efflux transporter P-glycoprotein and other extrusion pumps are present on the membrane surface of endothelial cells, juxtaposed toward the interior of the capillary. Furthermore, CNS endothelial cells display a net negative charge at the interior of the capillaries and at the basement membrane. This provides an additional selective mechanism by impeding passage of anionic molecules across the membrane. 

The inflammatory process initiated by locally produced proinflammatory cytokines induce or enhance the expression of several adhesion molecules [7,8,39,103]. The adhesion of leukocytes to the endothelial surface and their subsequent migration from the microvessels into the brain parenchyma are mediated by a variety of molecules located on the surface of both leukocytes and endothelial cells [7]. Adhesion molecules are divided into four main families integrins, the immunoglobulin superfamily, cadherins, and selectins [115]. Under normal conditions, there is little or no cell-surface expression of adhesion molecules [116]. Inflammatory processes, such as cerebral ischemia induce their expression with the upregulation mediated by cytokines [7]. They are glycoprotein in nature and are the anchors that mediate the attachment of leukocytes [117]. 

Dore-Dufly, P., Washington, R., and Dragovic, L., Expression of endothelial cell activation antigens in microvessels from patients with multiple sclerosis, in Frontiers in Cerebral Vascular Biology Transport and Its Regulation, Drewes, L. R. and Betz, A. L., Eds., Plenum Press, New York, 1993, 243. 

Figure9.12 (a) Cerebral capillary covered with astrocyte end-feet, (b) Cross section of a brain microvessel formed by endothelial cells, pericytes, and astrocyte end-feet (from Ref. [104]).

The blood-brain barrier (BBB) is a selective barrier formed by endothelial cells that hne the cerebral microvessels and is present in all vertebrate animals [ 1], It consists of a network of capillaries in the human brain with an approximately total length of 600 km and an average distance of 40 pm from each capillary [2]. 

FIGURE 14.2 Schematic of the cross-sectional view of (a) a peripheral microvessel (the microvessel in nonbrain organs), and (b) the blood-brain barrier (BBB) or cerebral microvessel (the microvessel in the brain). In addition to other structures as in a peripheral microvessel, the BBB is wrapped by astrocyte foot processes (AS, green). BM, basement membrane (or basal lamina) EC, endothelial cell N, nucleus of endothelial cell P, pericytes SGL, surface glycocalyx layer TJ, tight junction. 

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