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Results for “Paracrine Communication”

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PubMed2004

The airway cholinergic system: physiology and pharmacology.

The present review summarizes the current knowledge of the cholinergic systems in the airways with special emphasis on the role of acetylcholine both as neurotransmitter in ganglia and postganglionic parasympathetic nerves and as non-neuronal paracrine mediator. The different cholinoceptors, various nicotinic and muscarinic receptors, as well as their signalling mechanisms are presented. The complex ganglionic and prejunctional mechanisms controlling the release of acetylcholine are explained, and it is discussed whether changes in transmitter release could be involved in airway dysfunctions. The effects of acetylcholine on different target cells, smooth muscles, nerves, surface epithelial and secretory cells as well as mast cells are described in detail, including the receptor subtypes involved in signal transmission.

Acetylcholine↗
PubMed2004

Effects of adrenomedullin on cell proliferation in rat adventitia induced by lysophosphatidic acid.

Lysophosphatidic acid (LPA) is a bioactive phospholipid having growth factor-like activity on fibroblasts and is involved in cardiovascular diseases such as hypertension and heart failure by inducing vascular remodeling, characterized by fibroblast proliferation and migration in adventitia. Among various bioactive factors that LPA works with, adrenomedullin (ADM) is a multiple functional peptide with an important cytoprotective effect against cardiovascular damage. We studied rat aortic adventitia to explore the possible paracrine/autocrine interaction between endogenous ADM and LPA. LPA stimulation of the adventitia to secrete ADM and express its mRNA was concentration dependent. ADM inhibited LPA-induced proliferation in adventitial cells and attenuated the activity of mitogen-activated protein kinase (MAPK) stimulated by LPA. In contrast, treatment with specific antagonists of the ADM receptor potentiated the LPA-induced proliferation in adventitial cells. We concluded that LPA stimulates the adventitia to produce and secrete ADM, which in turn regulates the vascular biological effects of LPA.

Adrenomedullin↗
PubMed2004

Integrating rapid responses to 1,25-dihydroxyvitamin D3 with transcriptional changes in osteoblasts: Ca2+ regulated pathways to the nucleus.

It is well established that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment of target cells including osteoblasts activates both membrane-initiated rapid Ca2+ responses linked to influx through voltage sensitive Ca2+ channels (VSCCs) and longer term nuclear receptor-mediated changes in gene expression. We recently reported use of a cDNA microarray strategy to identify transcriptional changes after 3 and 24h of treatment with 1,25(OH)2D3 and with an analog of 1,25(OH)2D3 (25(OH)-16ene-23yne-D3 [AT]) that activates Ca2+ influx without binding to the nuclear receptor. Among 5000 different clones on the array filters, we identified families of genes in osteoblasts that were altered two-fold or greater following treatment with 1,25(OH)2D3 or analog AT for 3h. Cluster analysis further revealed complex patterns of changes in gene expression, indicative of multiple pathways to the nucleus. Evidenced by changes in target gene expression, activation of a Ca2+/CaMK/CREB/CRE pathway clearly occurs and modulates expression of a variety of genes associated with changes in protein secretion including those involved in paracrine regulation of bone resorption, RANKL and osteoprotegerin (OPG). The changes in gene expression can be inhibited by L-type VSCC channel blockers, confirming the role of Ca2+ entry in pathway activation. These findings provide clear evidence of rapid changes in gene expression associated with Ca2+ influx after treatment with 1,25(OH)2D3, and open the door to novel nuclear receptor-independent signaling pathways that affect gene transcription.

Animals↗
PubMed2005

Mechanisms of rhythmogenesis: insights from hypothalamic vasopressin neurons.

Many neurons in the CNS, including hypothalamic vasopressin-expressing cells, display rhythmic activity patterning. These vasopressin neurons receive random synaptic input but fire action potentials in alternating periods of activity and silence that each lasts tens of seconds. Recent work demonstrates that vasopressin cell rhythmicity depends on feedback modulation of intrinsic membrane properties and synaptic inputs by peptides released from the dendrites of these neurons. Many other neurons across the CNS release neurotransmitters from their dendrites; therefore, vasopressin cells provide an insight into the potential mechanisms that support neuronal activity patterning across the CNS.

Animals↗
PubMed2004

Paracrine role for periadventitial adipose tissue in the regulation of arterial tone.

Recent studies propose a paracrine role for periadventitial adipose tissue in the regulation of vascular tone. This regulation depends on the anatomical integrity of the periadventitial adipose tissue and involves adipocyte-derived relaxing factor (ADRF). Although the nature of ADRF is largely unknown, it is released by periadventitial adipocytes and induces vasorelaxation by opening K+ channels in the plasma membrane of smooth muscle cells. Alterations in the paracrine role of periadventitial adipose tissue might have a role in vascular dysfunction in hypertension and metabolic disease. Therefore, understanding alterations in ADRF release and the K+ channels involved will help further our understanding of the increased cardiovascular risk and development of chronic vascular disease in obesity. Furthermore, ADRF and perhaps its putative targets might represent exciting new targets for the development of drugs to treat cardiovascular disorders.

Adipose Tissue↗
PubMedDate not supplied

Intracoronary angiotensin II causes inotropic and vascular effects via different paracrine mechanisms.

We hypothesized that Angiotensin II (Ang II), like other circulating hormones, acts exclusively intravascularly. To activate or block solely intravascular Ang II receptors, Ang II and its peptide receptor blocker saralasin (Sar) were covalently coupled to a inert polymer (POL, MW >4000 kD) forming Ang II-POL and Sar-POL. These two nonpermeable polymers, Ang II and Sar, were intracoronarily administered into the isolated, saline-perfused rat hearts. Ang II-POL and Ang II caused a dose-dependent ventricular positive inotropic (+I) and vasoconstrictor effects (+V) which were blocked by Sar. Sar-POL blocked their +I but not their +V. Thus, Ang II and Ang II-POL act on endothelial luminal receptors through paracrine mechanisms. +I were blocked solely by purinoceptor antagonists and paralleled by augmented venous release of ATP degradation products (adenosine, inosine and hypoxanthine). In contrast, +V were blocked solely by aspirin, indomethacin or a thromboxane A2 receptor antagonist. Intracoronary administration of ATP-gamma-S and U46169, a purinergic, and TXA2 agonists, respectively, mimicked +I and +V. The results indicate that ATP is the paracrine inotropic mediator while thromboxane A2 is the vasoconstrictor mediator. Thus, the +I and +V distinct effects by intracoronary Ang II indicate that its diverse mechanism of action along the coronary vascular tree may be due to a functionally heterogeneous endothelium.

Angiotensin II↗
PubMed2005

Normal patterning of the coronary capillary plexus is dependent on the correct transmural gradient of FGF expression in the myocardium.

The formation of the coronary vessel system is vital for heart development, an essential step of which is the establishment of a capillary plexus that displays a density gradient across the myocardial wall, being higher on the epicardial than the endocardial side. This gradient in capillary plexus formation develops concurrently with transmural gradients of myocardium-derived growth factors, including FGFs. To test the role of the FGF expression gradient in patterning the nascent capillary plexus, an ectopic FGF-over-expressing site was created in the ventricular myocardial wall in the quail embryo via retroviral infection from E2-2.5, thus abolishing the transmural gradient of FGFs. In FGF virus-infected regions of the ventricular myocardium, the capillary density across the transmural axis shifted away from that in control hearts at E7. This FGF-induced change in vessel patterning was more profound at E12, with the middle zone becoming the most vascularized. An up-regulation of FGFR-1 and VEGFR-2 in epicardial and subepicardial cells adjacent to FGF virus-infected myocardium was also detected, indicating a paracrine effect on induction of vascular signaling components in coronary precursors. These results suggest that correct transmural patterning of coronary vessels requires the correct transmural expression of FGF and, therefore, FGF may act as a template for coronary vessel patterning.

Animals↗
PubMed2006

Post-implantation mouse conceptuses produce paracrine signals that regulate the uterine endometrium undergoing decidualization.

The uterus undergoes a series of dramatic changes in response to an implanting conceptus that, in some mammalian species, includes differentiation of the endometrial stroma into decidual tissue. This process, called decidualization, can be induced artificially in rodents indicating that the conceptus may not be essential for a proper maternal response in early pregnancy. In order to test this hypothesis, we determined if and how the conceptus affects uterine gene expression. We identified 5 genes (Angpt1, Angpt2, Dtprp, G1p2 and Prlpa) whose steady-state levels in the uterus undergoing decidualization depends on the presence of a conceptus. In situ hybridization revealed region-specific effects which suggested that various components of the conceptus and more than one signal from the conceptus are likely responsible for altering decidual cell function. Using cell culture models we found that trophoblast giant cells secrete a type I interferon-like molecule which can induce G1p2 expression in endometrial stromal cells. Finally, decidual Prlpa expression was reduced in the uterus adjacent to Hand1- and Ets2-deficient embryos, suggesting that normal trophoblast giant cells in the placenta are required for the conceptus-dependent effects on Prlpa expression in the mesometrial decidua. Overall, these results provide support for the hypothesis that molecular signals from the mouse conceptus have local effects on uterine gene expression during decidualization.

Angiopoietin-Like Protein 2↗
PubMed2005

Neural stem cells induce bone-marrow-derived mesenchymal stem cells to generate neural stem-like cells via juxtacrine and paracrine interactions.

Several recent reports suggest that there is far more plasticity that previously believed in the developmental potential of bone-marrow-derived cells (BMCs) that can be induced by extracellular developmental signals of other lineages whose nature is still largely unknown. In this study, we demonstrate that bone-marrow-derived mesenchymal stem cells (MSCs) co-cultured with mouse proliferating or fixed (by paraformaldehyde or methanol) neural stem cells (NSCs) generate neural stem cell-like cells with a higher expression of Sox-2 and nestin when grown in NS-A medium supplemented with N2, NSC conditioned medium (NSCcm) and bFGF. These neurally induced MSCs eventually differentiate into beta-III-tubulin and GFAP expressing cells with neuronal and glial morphology when grown an additional week in Neurobasal/B27 without bFGF. We conclude that juxtacrine interaction between NSCs and MSCs combined with soluble factors released from NSCs are important for generation of neural-like cells from bone-marrow-derived adherent MSCs.

Animals↗
PubMed2004

Endocrine and paracrine control of Leydig cell steroidogenesis and proliferation in the wall lizard: an in vitro study.

The present in vitro study, for the first time, demonstrates the endocrine as well as paracrine control of Leydig cell steroidogenesis and proliferation in the wall lizard Hemidactylus flaviviridis. Unlike mammals, Leydig cell activity in the wall lizard seems to be directly controlled by ovine follicle-stimulating hormone (FSH)-like molecule, since FSH increased the testosterone production and tritiated thymidine ([(3)H]TdR) incorporation by Leydig cells. In addition, Sertoli cell paracrine factor or factors play important roles in controlling Leydig cell activities as non-activated Sertoli cell-conditioned medium (SCCM) alone stimulated testosterone production by both non-activated and FSH-preactivated Leydig cells. As far as the proliferation was concerned, non-activated SCCM did not influence [(3)H]TdR uptake by non-activated or FSH-preactivated Leydig cells, while FSH-preactivated SCCM was able to stimulate proliferation of activated Leydig cells. It may be concluded that FSH, besides directly controlling, also regulates Leydig cell activities indirectly through stimulating the secretion of Sertoli cell paracrine factors. Moreover, steroidogenic factor is different from mitogenic factor because non-activated Leydig cells were responsive to steroidogenic factor but nonresponsive to mitogenic factor.

Animals↗
PubMed2006

Gender differences in injury induced mesenchymal stem cell apoptosis and VEGF, TNF, IL-6 expression: role of the 55 kDa TNF receptor (TNFR1).

Concomitant pro- and anti-inflammatory properties of bone marrow stem cells (BMSC) may be an important aspect of their ability to heal injured tissue. However, very few studies have examined whether gender differences exist in BMSC function. Indeed, it remains unknown whether gender differences exist in BMSC function and ability to resist apoptosis, and if so, whether TNF receptor 1 (TNFR1) plays a role in these differences. We hypothesized that TNFR1 ablation equalizes gender differences in bone marrow mesenchymal stem cell (MSC) apoptosis, as well as expression of vascular endothelial growth factor (VEGF), TNF and interleukin (IL)-6. Mouse MSCs from male wild type (WT), female WT, male TNFR1 knockouts (TNFR1KO) and female TNFR1KO were stressed by endotoxin 200 ng/ml or 1 h hypoxia. MSC activation was determined by measuring VEGF, TNF and IL-6 production (ELISA). Differences considered significant if p<0.05. LPS and hypoxia resulted in significant activation in all experimental groups compared to controls. Male WT demonstrated significantly greater TNF and IL-6 and significantly less VEGF release than female WT MSCs. However, release of TNF, IL-6 and VEGF in male TNFR1 knockouts differed from male WT, but was not different from female WT MSCs. Similarly apoptosis in hypoxic male TNFRIKO differed from male WT, but it was not different from apoptosis from WT female. Female WT did not differ in TNF, IL-6 and VEGF release compared to female TNFR1KO. Gender differences exist in injury induced BMSC VEGF, TNF and IL-6 expression. TNFR1 may autoregulate VEGF, TNF and IL-6 expression in males more than females. MSCs are novel therapeutic agents for organ protection, but further study of the disparate expression of VEGF, TNF and IL-6 in males and females as well as the role of TNFR1 in these gender differences is necessary to maximize this protection.

Animals↗
PubMed1999

Paracrine actions of cardiac fibroblasts on cardiomyocytes: implications for the cardiac renin-angiotensin system.

Conditioned medium of cardiac fibroblasts was found to induce protein synthesis and signal transduction events rapidly, and to increase angiotensinogen messenger RNA (mRNA) levels in neonatal rat ventricular myocytes. Within 4 hours, fibroblast-conditioned medium (FCM) stimulated protein synthesis in cardiac myocytes, independent of the contractile state, and induced marked increases within 24 hours in total protein content. Endothelin- released by cardiac fibroblasts was not responsible for the stimulation of protein synthesis. FCM rapidly activated signal transduction events in cardiac myocytes associated with hypertrophic stimuli, including: (1) increased tyrosine phosphorylation of several prominent protein bands; (2) mitogen-activated protein kinases (ERK 1 and ERK 2); and (3) protein kinase C. Finally, FCM caused an increase at 8 hours in angiotensinogen mRNA levels of cardiac myocytes, whereas no effect was observed on mRNA levels for renin or the type 1 angiotensin II receptor (AT1). Our results suggest that cardiac fibroblasts produce a factor that rapidly activates cardiac myocyte growth through a membrane receptor that couples to conventional signal transduction pathways.

Angiotensinogen↗
PubMed2001

Interleukin-8 is a paracrine inducer of fibroblast growth factor 2, a stromal and epithelial growth factor in benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is an extremely common disease of older men in which there is benign overgrowth of the prostatic transition zone, leading to obstruction of urine outflow. Fibroblast growth factor (FGF) 2, a potent growth factor for prostatic stromal and epithelial cells, is increased twofold in BPH and its concentration is correlated with stromal proliferation in this condition. Immunohistochemistry of normal and hyperplastic prostate revealed that FGF2-expressing stromal cells were present in higher numbers near the epithelial acini, implying that epithelial cells may express a factor that induces FGF2 expression by stromal cells. Conditioned medium from primary cultures of prostatic epithelial cells was capable of inducing increased expression of FGF2 by primary stromal cultures. Blocking experiments with neutralizing anti-interleukin (IL)-8 antibodies and pretreatment with lipopolysaccharide, which down-regulates the IL-8 receptor, show that this inducing activity is because of the presence of IL-8 in the epithelial-conditioned medium. Analysis of normal prostatic peripheral zone and BPH tissue by enzyme-linked immunosorbent assay reveals that IL-8 is present at increased levels in hyperplastic prostate. Therefore IL-8 produced by prostatic epithelial cells can induce FGF2, a potent stromal and epithelial growth factor, and in this manner promote the abnormal proliferation of the prostatic transition zone that is critical in the pathogenesis of BPH.

Cells, Cultured↗
PubMed2003

Hepatocytes express nerve growth factor during liver injury: evidence for paracrine regulation of hepatic stellate cell apoptosis.

A key feature of recovery from liver fibrosis is hepatic stellate cell (HSC) apoptosis, which serves the dual function of removing the major source of neomatrix and tissue inhibitors of metalloproteinases thereby facilitating matrix degradation. The mechanisms regulating HSC apoptosis remain undefined but may include the interaction of nerve growth factor (NGF) with its receptor, p75, on HSC. In this study, by TaqMan polymerase chain reaction in situ hybridization and immunohistochemistry, we demonstrate that NGF is expressed by hepatocytes during fibrotic injury. Peak hepatocyte expression of NGF (48 hours after CCl(4) injection) coincides with maximal rate of apoptosis of HSC by terminal dUTP nick-end labeling staining. Addition of recombinant NGF to HSC in tissue culture causes a dose-dependent increase in apoptosis. NGF regulates nuclear factor (NF)-kappaB activity, reducing p50/p65 binding detected by electromobility shift assay and reduced NF-kappaB CAT reporter activities from both basal unstimulated levels and after NF-kappaB induction by tumor necrosis factor. In each case, a relative reduction in NF-kappaB binding was associated with a significant increase in caspase 3 activity. These data provide evidence that NGF is expressed during fibrotic liver injury and may regulate number of activated HSCs via induction of apoptosis.

Animals↗
PubMed2000

Interleukin-1alpha is a paracrine inducer of FGF7, a key epithelial growth factor in benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is an extremely common disease of older men in which there is benign overgrowth of the prostatic transition zone, leading to obstruction of urine outflow. FGF7, a potent growth factor for prostatic epithelial cells, is increased by threefold in BPH and is correlated with increased epithelial proliferation in this condition. Immunohistochemistry of normal and hyperplastic prostate revealed that FGF7-expressing fibroblastic cells were present in higher numbers near the epithelial acini, implying that epithelial cells may express a factor that induces FGF7 expression by stromal cells. Conditioned medium (CM) from primary cultures of prostatic epithelial cells was capable of inducing a two- to sixfold increase in the expression of FGF7 by primary stromal cultures. Blocking experiments with neutralizing anti-interleukin-1alpha (Il-1alpha) antibodies and IL-1Ra, an Il-1alpha receptor antagonist, show that this inducing activity was due to the presence of Il-1alpha in the epithelial CM. Analysis of normal prostatic peripheral zone and BPH tissue by enzyme-linked immunoabsorption assay reveal that Il-1alpha is present at increased levels in hyperplastic prostate and that levels of Il-1alpha correlate strongly with tissue FGF7 concentration in BPH. Therefore Il-1alpha is produced by prostatic epithelial cells and can induce FGF7, a potent epithelial growth factor, which can in turn lead to further epithelial growth and increased Il-1alpha secretion, thus establishing a double paracrine loop that is functionally equivalent to an autocrine growth loop. This double paracrine loop may play a key role in the abnormal proliferation of the transition zone, which is critical to the pathogenesis of BPH.

Cells, Cultured↗
PubMed1999

Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation.

The retinal pigment epithelium (RPE) maintains the choriocapillaris (CC) in the normal eye and is involved in the pathogenesis of choroidal neovascularization in age-related macular degeneration. Vascular endothelial growth factor-A (VEGF) is produced by differentiated human RPE cells in vitro and in vivo and may be involved in paracrine signaling between the RPE and the CC. We investigated whether there is a polarized secretion of VEGF by RPE cells in vitro. Also, the localization of VEGF receptors in the human retina was investigated. We observed that highly differentiated human RPE cells, cultured on transwell filters in normoxic conditions, produced two- to sevenfold more VEGF toward their basolateral side as compared to the apical side. In hypoxic conditions, VEGF-A secretion increased to the basal side only, resulting in a three- to 10-fold higher basolateral secretion. By immunohistochemistry in 30 human eyes and in two cynomolgus monkey eyes, KDR (VEGFR-2) and flt-4 (VEGFR-3) were preferentially localized at the side of the CC endothelium facing the RPE cell layer, whereas flt-1 (VEGFR-1) was found on the inner CC and on other choroidal vessels. Our results indicate that RPE secretes VEGF toward its basal side where its receptor KDR is located on the adjacent CC endothelium, suggesting a role of VEGF in a paracrine relation, possibly in cooperation with flt-4 and its ligand. This can explain the known trophic function of the RPE in the maintenance of the CC and its fenestrated permeable phenotype and points to a role for VEGF in normal eye functioning. Up-regulated basolateral VEGF secretion by RPE in hypoxia or loss of polarity of VEGF production may play a role in the pathogenesis of choroidal neovascularization.

Adolescent↗
PubMed1999

Abundant production of brain-derived neurotrophic factor by adult visceral epithelia. Implications for paracrine and target-derived Neurotrophic functions.

Brain-derived neurotrophic factor (BDNF) plays a crucial role for the survival of visceral sensory neurons during development. However, the physiological sources and the function of BDNF in the adult viscera are poorly described. We have investigated the cellular sources and the potential role of BDNF in adult murine viscera. We found markedly different amounts of BDNF protein in different organs. Surprisingly, BDNF levels in the urinary bladder, lung, and colon were higher than those found in the brain or skin. In situ hybridization experiments revealed that BDNF mRNA was made by visceral epithelial cells, several types of smooth muscle, and neurons of the myenteric plexus. Epithelia that expressed BDNF lacked both the high- and low-affinity receptors for BDNF, trkB and p75(NTR). In contrast, both receptors were present on neurons of the peripheral nervous system. Studies with BDNF-/-mice demonstrated that epithelial and smooth muscle cells developed normally in the absence of BDNF. These data provide evidence that visceral epithelia are a major source, but not a target, of BDNF in the adult viscera. The abundance of BDNF protein in certain internal organs suggests that this neurotrophin may regulate the function of adult visceral sensory and motor neurons.

Animals↗