Role of AM in Blood Brain Barrier Functions

Among the endothelial cells of different tissues, the endothelium of the brain is very specific. Although cerebral endothelial cells (CECs) share many common properties of the peripheral endothelium, they have a unique morphological and functional feature, the formation of the BBB. The BBB contributes to the stability of the brain parenchymal microenvironment by strictly controlling the traffic of molecules and cells between the blood and the central nervous system. The BBB has specific, epithelial cell-like morphological characteristics and physical barrier properties, such as tight intercellular junctions, the absence of intercellular clefts, low rate of pinocytosis, many mitochondria, continuous basement membrane, or high transendothelial electrical resistance. Specific, polarized, highly discriminatory membrane transport systems, such as glucose transporter-1, nucleoside transport system, or large neutral amino acid transporter, operate to supply the brain. Efflux transporters, such as P-glycoprotein or members of multidrug-resistance protein family (MRP-1, -3, -4, -5, -6), can eliminate toxic substances from endothelial compartments and brain. The BBB phenotype of CECs is induced by the astroglial environment. Although the effect of neurons on the induction of some specific CEC properties have been described, the effect of astroglia on CECs in vitro has been more extensively studied.

The involvement of cAMP in the regulation of BBB functions has long been known; for example, cAMP elevates transendothelial electrical resistance and decreases paracellular permeability, reduces the rate of fluid-phase endocytosis, and increases P-glycoprotein function. It has been proved that AM has cAMP-like effects on specific BBB functions in vitro [6]. Exogenous AM increased trans-endothelial electrical resistance and reduced endothelial permeability for the low-molecular-weight sodium fluorescein, which suggests a tightening of intercellular junctions. AM also decreased endothelial fluid-phase endocytosis, a type of nonspecific endothelial transport, although it did not change the transendothelial albumin permeability. AM activated the P-glycoprotein efflux pump, while it did not change the activity of MRP-1 efflux transporter in cultures of rat CECs. Treatment with either the AM receptor antagonist AM22-52 or the AM antisense oligonucleotide decreased the basal intracellular cAMP level in rat CECs. Michibata et al. [7] have reported that neutralization of endogenous AM by monoclonal antibodies reduced the basal cAMP production in bovine aortic endothelial cells. In primary rat CECs antisense treatment significantly reduced the AM production and decreased transendothelial electrical resistance [6]. It is remarkable that the basal intracellular cAMP concentration is the highest in rat CECs followed by GP8-immortalized rat CECs and human umbilical vein endothelial cells, which corresponds to the AM production of these cells. These observations suggest that AM, as an autocrine mediator, plays an important role in the maintenance of basal intraendothelial cAMP levels, and AM appears to be an autocrine inducer of BBB functions of CECs via the activation of adenylate cyclase enzyme. Moreover, astrocyte-derived factors increased the AM production by primary rat CECs, suggesting that AM is involved in the astrocytic regulation of the BBB phenotype. Therefore, AM can be a physiological link between astrocyte-derived factors, cAMP, and the induction and maintenance of the BBB properties by rat CECs (Figure 1).

Figure 1 Adrenomedullin and the BBB. Adrenomedullin production in cerebral endothelial cells is stimulated by unknown astrocyte-derived factors. The synthesized adrenomedullin is secreted mostly at the luminal surface of the cerebral endothelial cells into the blood, but also at the ablu-minal surface. The released peptide acts as an autocrine/paracrine hormone and stimulates cAMP production in the cells. The elevated intracellular cAMP will improve the barrier functions of the cerebral endothelial cells. EC, cerebral endothelial cell; PC, pericytes, TJ, tight interendothelial junction; AM-R, adrenomedullin receptor.

Figure 1 Adrenomedullin and the BBB. Adrenomedullin production in cerebral endothelial cells is stimulated by unknown astrocyte-derived factors. The synthesized adrenomedullin is secreted mostly at the luminal surface of the cerebral endothelial cells into the blood, but also at the ablu-minal surface. The released peptide acts as an autocrine/paracrine hormone and stimulates cAMP production in the cells. The elevated intracellular cAMP will improve the barrier functions of the cerebral endothelial cells. EC, cerebral endothelial cell; PC, pericytes, TJ, tight interendothelial junction; AM-R, adrenomedullin receptor.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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