Adrenomedullin, an Autocrine Mediator of Blood-Brain Barrier Function

Kis, Béla; Ábrahám, Csongor S.; Deli, Mária A.; Kobayashi, Hideyuki; Níwa, Masami; Yamashita, Hiroshi; Busija, David W.; Ueta, Yoichi

doi:10.1291/hypres.26.s61

Cited by 40 publications

(23 citation statements)

References 131 publications

(169 reference statements)

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“…AM has a known ability to regulate its receptor components [26], hence CLR, RAMP2 and RAMP3 production in primary human CD3 + T cells was investigated following 24 h treatment with AM. Considering increased AM levels during inflammation [13,32] and hypoxia conditions [17,27], a pathological concentration of 10 − 6 M was selected in line with previous experiments on the blood-brain barrier [33] and cerebral endothelia cells [1]. Our study revealed a modest activationdependent down-regulation of RAMP2 (PHA+/cell surface) and RAMP3 (PHA-/internal) following exposure to AM.…”

Section: Discussionmentioning

confidence: 77%

Adrenomedullin receptors on human T cells are glucocorticoid-sensitive

Liverani

McLeod

Paul

2012

International Immunopharmacology

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Adrenomedullin (AM) is a novel vasodilatatory peptide which acts primarily through the calcitonin receptor-like receptor (CLR) in combination with either receptor-activity-modifying-protein (RAMP) 2 or 3 (forming receptors, AM(1) and AM(2) respectively). AM plays an important role during inflammation, with its expression increasing following cytokine treatment, promoting macrophage action in situ and high expression by T cells during hypoxic conditions. Examination of T cell AM receptor expression has previously been incomplete, hence we here consider the presentation of AM receptors and their responsiveness to AM and glucocorticoids (GC). AM receptor expression was examined by PCR and flow cytometry in primary human T cells, revealing that RAMP2, 3 and CLR are physiologically expressed in unstimulated T cells, both intracellularly and on the cell surface. PHA stimulation decreased receptor proteins, significantly so for CLR and RAMP3. Incubation with AM elicited limited receptor alterations however, GC treatment (10(-6) M; 24 h) markedly affected cell surface expression, significantly increasing receptor components in unstimulated cells and significantly decreasing the same in stimulated T cells. Our findings indicate that human T cells utilize both AM(1) and AM(2) receptors, which are GC-sensitive in an activation-state dependent manner.

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Section: Discussionmentioning

confidence: 77%

Adrenomedullin receptors on human T cells are glucocorticoid-sensitive

Liverani

McLeod

Paul

2012

International Immunopharmacology

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“…cAMP is an autocrine mediator which maintains the intraendothelial cyclic cAMP levels, and it is also known to be a critical regulator of BBB (Kis et al, 2003a).…”

Section: Discussionmentioning

confidence: 99%

“…The AM gene is thus expressed in and the peptide is released by various cells and it is thus considered to play a pathological role in cerebrovascular and cardiovascular diseases Fujioka et al, 2000;Terata et al, 2000;Kastin et al, 2001;Wijdicks et al, 2001;Kis et al, 2001aKis et al, ,b, 2002Kis et al, , 2003aSerrano et al, 2002;Kato et al, 2003;Tahan et al, 2003;Fernandez-Sauze et al, 2004;Hayashi et al, 2004;Nagoshi et al, 2004;Suzuki et al, 2004). AM is also secreted from cultured rat brain microvascular endothelial cells (BMEC) and its production is stimulated by astrocyte-derived factors (Kis et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Adrenomedullin Improves the Blood–Brain Barrier Function Through the Expression of Claudin-5

et al. 2006

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“…To increase junctional integrity, we used adrenomedullin and the cAMP analog 8-pCPT-29-O-Me-cAMP (O-Me). Whereas adrenomedullin is a crucial autocrine and paracrine hormone mediator of blood-brain-barrier junctional tightness (Kis et al, 2003), O-Me acts downstream of adrenomedullin by directly stimulating the guanine nucleotide exchange factor EPAC-1 (also known as RAPGEF3), which, in turn, activates the small GTPase Rap-1 and, ultimately, Rac-1 (Bos, 2003;Spindler et al, 2010). Addition of adrenomedullin or O-Me to rat brain endothelium led to a ,15% enhancement in the already high (,77 Vcm 2 ) resistance ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Probing the biomechanical contribution of the endothelium to lymphocyte migration: diapedesis by the path of least resistance

Martinelli

Zeiger

Whitfield

et al. 2014

Journal of Cell Science

103

148

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Immune cell trafficking requires the frequent breaching of the endothelial barrier either directly through individual cells ('transcellular' route) or through the inter-endothelial junctions ('paracellular' route). What determines the loci or route of breaching events is an open question with important implications for overall barrier regulation. We hypothesized that basic biomechanical properties of the endothelium might serve as crucial determinants of this process. By altering junctional integrity, cytoskeletal morphology and, consequently, local endothelial cell stiffness of different vascular beds, we could modify the preferred route of diapedesis. In particular, high barrier function was associated with predominantly transcellular migration, whereas negative modulation of junctional integrity resulted in a switch to paracellular diapedesis. Furthermore, we showed that lymphocytes dynamically probe the underlying endothelium by extending invadosome-like protrusions (ILPs) into its surface that deform the nuclear lamina, distort actin filaments and ultimately breach the barrier. Fluorescence imaging and pharmacologic depletion of F-actin demonstrated that lymphocyte barrier breaching efficiency was inversely correlated with local endothelial F-actin density and stiffness. Taken together, these data support the hypothesis that lymphocytes are guided by the mechanical 'path of least resistance' as they transverse the endothelium, a process we term 'tenertaxis'.

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Adrenomedullin, an Autocrine Mediator of Blood-Brain Barrier Function

Cited by 40 publications

References 131 publications

Adrenomedullin receptors on human T cells are glucocorticoid-sensitive

Adrenomedullin receptors on human T cells are glucocorticoid-sensitive

Adrenomedullin Improves the Blood–Brain Barrier Function Through the Expression of Claudin-5

Probing the biomechanical contribution of the endothelium to lymphocyte migration: diapedesis by the path of least resistance

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