scholarly journals Chronic hypoxia alters fetal cerebrovascular responses to endothelin-1

2017 ◽  
Vol 313 (2) ◽  
pp. C207-C218 ◽  
Author(s):  
Jinjutha Silpanisong ◽  
Dahlim Kim ◽  
James M. Williams ◽  
Olayemi O. Adeoye ◽  
Richard B. Thorpe ◽  
...  
Keyword(s):  
Organ Culture ◽  
Muscle Hypertrophy ◽  
Chronic Hypoxia ◽  
Cerebral Arteries ◽  
Cerebrovascular Reactivity ◽  
Dependent Manner ◽  
Ki 67 ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
And Function

In utero hypoxia influences the structure and function of most fetal arteries, including those of the developing cerebral circulation. Whereas the signals that initiate this hypoxic remodeling remain uncertain, these appear to be distinct from the mechanisms that maintain the remodeled vascular state. The present study explores the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to endothelin-1 (ET-1), a potent vascular contractant and mitogen. In fetal lambs, chronic hypoxia (3,820-m altitude for the last 110 days of gestation) had no significant effect on plasma ET-1 levels or ETA receptor density in cerebral arteries but enhanced contractile responses to ET-1 in an ETA-dependent manner. In organ culture (24 h), 10 nM ET-1 increased medial thicknesses less in hypoxic than in normoxic arteries, and these increases were ablated by inhibition of PKC (chelerythrine) in both normoxic and hypoxic arteries but were attenuated by inhibition of CaMKII (KN93) and p38 (SB203580) in normoxic but not hypoxic arteries. As indicated by Ki-67 immunostaining, ET-1 increased medial thicknesses via hypertrophy. Measurements of colocalization between MLCK and SMαA revealed that organ culture with ET-1 also promoted contractile dedifferentiation in normoxic, but not hypoxic, arteries through mechanisms attenuated by inhibitors of PKC, CaMKII, and p38. These results support the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to ET-1 through pathways dependent upon PKC, CaMKII, and p38 that cause increased ET-1-mediated contractility, decreased ET-1-mediated smooth muscle hypertrophy, and a depressed ability of ET-1 to promote contractile dedifferentiation.

Human Endothelin Subtype A Receptor Enhancement during Tissue Culture via de Novo Transcription

Neurosurgery ◽  
2002 ◽  
Vol 50 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Jacob Hansen-Schwartz ◽  
Carl-Henrik Nordström ◽  
Lars Edvinsson
Keyword(s):  
Organ Culture ◽  
Receptor Antagonist ◽  
De Novo ◽  
Cerebral Arteries ◽  
Maximal Response ◽  
Messenger Ribonucleic Acid ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

ABSTRACT OBJECTIVE Endothelin (ET) has, since its discovery, increasingly been considered a key player in the pathophysiological processes of cerebral vasospasm in the course of subarachnoid hemorrhage, although it remains unclear how ET is involved. We present data that indicate an inherent capacity of human cerebral arteries to change their sensitivity to ET. METHODS Human cerebral arteries were obtained from patients undergoing intracranial tumor surgery. The vessels were divided into segments and subjected to organ culture for 48 hours. The vessels were then examined by using in vitro pharmacological methods and molecular biological techniques. RESULTS After organ culture of the cerebral arteries, both the sensitivity to and potency of ET were enhanced (maximal response, 152 ± 9%; −log (50% effective concentration), 10.3 ± 0.3), in comparison with data for fresh cerebral arteries. Contractions were inhibited by both FR139317 (a specific ETA receptor antagonist) and bosentan (a mixed ETA and ETB receptor antagonist), in a manner indicating the sole presence of contractile ETA receptors. An inconsistent dilative response to the selective ETB receptor agonist sarafotoxin 6c was observed; the response was preserved in some segments and abolished in others, and potentiation of the precontraction was observed in yet other segments. No isolated contractile response to sarafotoxin 6c was observed, however. In reverse transcription-polymerase chain reaction assays, both ETA and ETB receptor messenger ribonucleic acid was detected. CONCLUSION These results demonstrate that human cerebral arteries are capable of enhancing the function of ETA receptors.

Function and survival of dendritic cells depend on endothelin-1 and endothelin receptor autocrine loops

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 2107-2115 ◽  
Author(s):  
Georgi Guruli ◽  
Beth R. Pflug ◽  
Stefana Pecher ◽  
Valeria Makarenkova ◽  
Michael R. Shurin ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Endothelin Receptors ◽  
Interleukin 12 ◽  
Endothelin 1 ◽  
Selective Blockade ◽  
Biologic Effects ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Major Antigen ◽  
And Function

Abstract The biologic effects of endothelin-1 (ET-1) are not limited to its potent vasoconstricting activity. The endothelin receptors, ETA and ETB, have differential tissue and functional distributions. Here we showed that dendritic cells (DCs), the major antigen-presenting cells in the adaptive limb of the immune system, produce large amounts of ET-1 and significantly increase the expression of endothelin receptors upon maturation. Selective blockade of the ETA receptor significantly reduced expression of the mature DC marker CD83, decreased the production of the immunostimulatory cytokine interleukin-12, down-regulated DC ability to stimulate T cells, and promoted DC apoptosis. Selective ETB receptor blockade, on the other hand, resulted in increased expression of CD83 and improved DC survival. Therefore, ET-1/ETA/ETB autocrine/paracrine loops on DCs appear to be essential for the normal maturation and function of human DCs, presenting a unique target for immunomodulatory therapies. (Blood. 2004;104:2107-2115)

Abstract 297: Increased ETA Receptor-Mediated Contractility of Thoracic Aorta by Endothelin-1 in High-Fat-Diet--Fed Insulin-Resistant Rats

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Ramarao Poduri ◽  
Payal Gupta ◽  
Anil Gulati
Keyword(s):  
Insulin Resistance ◽  
Thoracic Aorta ◽  
High Fat Diet ◽  
Specific Binding ◽  
Dependent Manner ◽  
High Fat ◽  
Contractile Responses ◽  
Endothelin 1 ◽  
Insulin Resistant ◽  
Eta Receptor

Abstract: Increased incidences of cardio-vascular complications in diabetic conditions are a major concern. Endothelin-1 (ET-1) is an important regulator of vascular contractility, and its effects are mediated through ETA and ETB. Previous data from the lab indicates that GPCR mediate contractile responses are enhanced and the present study is aimed to extend the hypothesis that ETA receptor mediated contractile responses of ET-1 under insulin-resistant condition are enhanced. Methods: Male Sprague-Dawley (SD) rats were kept on high-fat diet (HFDIRR, 8 weeks) for inducing insulin-resistance. Further, b-cell specific toxin streptozotocin (STZ, 50 mg/kg; i.p.) was used to induce hypoinsulinemia in rats. The responses of ET-1, ACh, KCl and Ang -II were recorded in the concentration-dependent manner in the thoracic aorta of rats. Specific ETA receptor antagonist, BMS182874 was used to confirm the findings. Specific binding of [3H]-BQ123 was performed to determine the characteristics of ETA receptors. Biochemical parameters were measured and induction of insulin-resistance was confirmed by intra-peritoneal glucose tolerance test (IPGTT). Results: ET-1 mediated contractile response (4541 ± 274 mg/mm2 (mean ± s.e.m. (n=8)) was significantly higher in insulin-resistant rats, while that of KCl unchanged. Tempol (100μM) restored the ET-1 mediated contractions in HFDIRR (4541 ± 274 vs 3406 ± 252.8 mg/mm2; p < 0.001; (n=5)). BMS182874 restored NO-mediated endothelium-dependent ACh relaxation in HFDIRR. The specific binding of [3H]-BQ123 to ETA receptors (112.35 ± 5.19 vs. 39.74 ± 4.04 f mol/mg; P < 0.001; (n=5)) was increased in HFDIRR. Conclusions: Insulin-resistance up-regulates ETA receptor may be responsible enhanced ET-1 mediated contractility of the thoracic aorta.

Effect of pentobarbital on the reactivity of isolated human cerebral arteries

1981 ◽  
Vol 54 (4) ◽  
pp. 521-524 ◽  
Author(s):  
Jesús Marín ◽  
Ramiro D. Lobato ◽  
Mercedes L. Rico ◽  
Mercedes Salaices ◽  
Julio Benitez
Keyword(s):  
Contractile Activity ◽  
Cerebral Arteries ◽  
Cerebrovascular Reactivity ◽  
Mechanical Activity ◽  
Dependent Manner ◽  
Content Type ◽  
Basal Tone ◽  
Dose Dependent ◽  
Arterial Tone ◽  
Fine Print

✓ The authors have analyzed the effect of pentobarbital (10−5M to 10−3M) on the contractile activity of isolated human cerebral arteries. Pentobarbital was found to inhibit both the spontaneous mechanical activity and the basal tone of these vessels. Relaxation induced by this drug was dose-dependent, and was more marked when the arterial tone was previously increased with noradrenalin, potassium chloride, or 5-hydroxytryptamine. In addition, pentobarbital inhibits, in a dose-dependent manner, the contractions elicited by these vasoconstrictor agents. The present findings indicate that barbiturates decrease cerebrovascular reactivity, and disagree with the hypothesis that these drugs reduce raised intracranial pressure by means of exerting a direct constrictive effect on the cerebral arteries.

Age-dependent modulation of endothelium-dependent vasodilatation by chronic hypoxia in ovine cranial arteries

2006 ◽  
Vol 100 (1) ◽  
pp. 225-232 ◽  
Author(s):  
James M. Williams ◽  
William J. Pearce
Keyword(s):  
Smooth Muscle ◽  
Chronic Hypoxia ◽  
Cerebral Arteries ◽  
Volume Of Distribution ◽  
Small Contribution ◽  
Age Dependent ◽  
Nonpregnant Adult ◽  
And Function ◽  
Chronic Hypoxemia

Although abundant evidence indicates that chronic hypoxia can induce pulmonary vascular remodeling, very little is known of the effects of chronic hypoxia on cerebrovascular structure and function, particularly in the fetus. Thus the present study explored the hypothesis that chronic hypoxemia also influences the size and shape of cerebrovascular smooth muscle and endothelial cells, with parallel changes in the reactivity of these cells to endothelium-dependent vasodilator stimuli. To test this hypothesis, measurements of endothelial and vascular smooth muscle cell size and density were made in silver-stained common carotid and middle cerebral arteries from term fetal and nonpregnant adult sheep maintained at an altitude of 3,820 m for 110 days. Chronic hypoxia induced an age-dependent remodeling that led to smooth muscle cells that were larger in fetal arteries but smaller in adult arteries. Chronic hypoxia also increased endothelial cell density in fetal arteries but reduced it in adult arteries. These combined effects resulted in an increased (adult carotid), decreased (adult middle cerebral), or unchanged (fetal arteries) per cell serosal volume of distribution for endothelial factors. Despite this heterogeneity, the magnitude of endothelium-dependent vasodilatation to A23187 , measured in vitro, was largely preserved, although sensitivity to this relaxant was uniformly depressed. NG-nitro-l-arginine methyl ester, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, and endothelium denudation each independently blocked A23187 -induced vasodilation without unmasking any residual vasoconstrictor effect. Indomethacin did not significantly attenuate A23187 -induced relaxation except in the hypoxic adult middle cerebral, where a small contribution of prostanoids was evident. Vascular sensitivity to exogenous nitric oxide (NO) was uniformly increased by chronic hypoxia. From these results, we conclude that chronic hypoxia reduced endothelial NO release while also upregulating some component of the NO-cGMP-PKG vasodilator pathway. These offsetting effects appear to preserve endothelium-dependent vasodilation after adaptation to chronic hypoxia.

scholarly journals Role of Endothelin-1 in the Migration of Human Olfactory Gonadotropin-Releasing Hormone-Secreting Neuroblasts

Endocrinology ◽  
2005 ◽  
Vol 146 (10) ◽  
pp. 4321-4330 ◽  
Author(s):  
Roberto G. Romanelli ◽  
Tullio Barni ◽  
Mario Maggi ◽  
Michaela Luconi ◽  
Paola Failli ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Migratory Pattern ◽  
Biochemical Analyses ◽  
Eta Receptor Antagonist ◽  
Dose Dependent

FNC-B4 neuroblasts that express both neuronal and olfactory markers have been established and cloned. These cells express GnRH and both the endothelin-1 (ET-1) gene and protein and respond in a migratory manner to GnRH in a dose-dependent manner. Previous research has shown that FNC-B4 cells produce and respond to ET-1 by regulating the secretion of GnRH through endothelin type A receptors and by stimulating their proliferation through endothelin type B (ETB) receptors. In this study, we found that FNC-B4 cells are able to migrate in response to ET-1 through the involvement of ETB receptors. Combined immunohistochemical and biochemical analyses showed that ET-1 triggered actin cytoskeletal remodeling and a dose-dependent increase in migration (up to 6-fold). Whereas the ETB receptor antagonist (B-BQ788) blunted the ET-1-induced effects, the ETA receptor antagonist (A-BQ123) did not. Moreover, we observed that FNC-B4 cells were independently and selectively stimulated by ET-1 and GnRH. We suggest that ET-1, through ETB receptor activation, may be required to maintain an adequate proliferative stem cell pool in the developing olfactory epithelium and the subsequent commitment to GnRH neuronal migratory pattern. The coordinate interaction between ET receptors and GnRH receptor participates in the fully expressed GnRH-secreting neuron phenotype.

Hypoxic regulation of the fetal cerebral circulation

2006 ◽  
Vol 100 (2) ◽  
pp. 731-738 ◽  
Author(s):  
William Pearce
Keyword(s):  
Cerebral Circulation ◽  
Chronic Hypoxia ◽  
Acute Hypoxia ◽  
Periventricular Leukomalacia ◽  
Cerebral Arteries ◽  
Fetal Brain ◽  
Respiratory Drive ◽  
Vascular Effect ◽  
Brain Structure And Function ◽  
And Function

Fetal cerebrovascular responses to acute hypoxia are fundamentally different from those observed in the adult cerebral circulation. The magnitude of hypoxic vasodilatation in the fetal brain increases with postnatal age although fetal cerebrovascular responses to acute hypoxia can be complicated by age-dependent depressions of blood pressure and ventilation. Acute hypoxia promotes adenosine release, which depresses fetal cerebral oxygen consumption through action of adenosine on neuronal A1 receptors and vasodilatation through activation of A2 receptors on cerebral arteries. The vascular effect of adenosine can account for approximately half the vasodilatation observed in response to hypoxia. Hypoxia-induced release of nitric oxide and opioids can account for much of the adenosine-independent cerebral vasodilatation observed in response to hypoxia in the fetus. Direct effects of hypoxia on cerebral arteries account for the remaining fraction, although the vascular endothelium contributes relatively little to hypoxic vasodilatation in the immature cerebral circulation. In contrast to acute hypoxia, fetal cerebral blood flow tends to normalize during acclimatization to chronic hypoxia even though cardiac output is depressed. However, uncompensated chronic hypoxia in the fetus can produce significant changes in brain structure and function, alteration of respiratory drive and fluid balance, and increased incidence of intracranial hemorrhage and periventricular leukomalacia. At the level of the fetal cerebral arteries, chronic hypoxia increases protein content and depresses norepinephrine release, contractility, and receptor densities associated with contraction but also attenuates endothelial vasodilator capacity and decreases the ability of ATP-sensitive and calcium-sensitive potassium channels to promote vasorelaxation. Overall, fetal cerebrovascular adaptations to chronic hypoxia appear prioritized to conserve energy while preserving basic contractility. Many gaps remain in our understanding of how the effects of acute and chronic hypoxia are mediated in fetal cerebral arteries, but studies of adult cerebral arteries have produced many powerful pharmacological and molecular tools that are simply awaiting application in studies of fetal cerebral artery responses to hypoxia.

scholarly journals Chronic Hypoxia Alters the Response of Fetal Ovine Middle Cerebral Arteries to Endothelin‐1 (ET‐1)

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Jinjutha Silpanisong ◽  
Dahlim Kim ◽  
James Williams ◽  
Olayemi Adeoye ◽  
Richard Thorpe ◽  
...  
Keyword(s):  
Chronic Hypoxia ◽  
Cerebral Arteries ◽  
Endothelin 1 ◽  
Middle Cerebral Arteries

scholarly journals Effects of chronic hypoxia on soluble guanylate cyclase activity in fetal and adult ovine cerebral arteries

2009 ◽  
Vol 107 (1) ◽  
pp. 192-199 ◽  
Author(s):  
William J. Pearce ◽  
James M. Williams ◽  
Charles R. White ◽  
Thomas M. Lincoln
Keyword(s):  
Guanylate Cyclase ◽  
Chronic Hypoxia ◽  
Soluble Guanylate Cyclase ◽  
Specific Activity ◽  
Cerebral Arteries ◽  
Cerebrovascular Reactivity ◽  
Pulmonary Vasculature ◽  
General Hypothesis ◽  
Cgmp Analog ◽  
Broad Variety

A broad variety of evidence obtained largely in pulmonary vasculature suggests that chronic hypoxia modulates vasoreactivity to nitric oxide (NO). The present study explores the general hypothesis that chronic hypoxia also modulates cerebrovascular reactivity to NO, and does so by modulating the activity of soluble guanylate cyclase (sGC), the primary target for NO in vascular smooth muscle. Pregnant and nonpregnant ewes were maintained at either sea level or at 3,820 m for the final 110 days of gestation, at which time middle cerebral arteries from term fetal lambs and nonpregnant adults were harvested. In both fetal and adult arteries, NO-induced vasodilatation was attenuated by chronic hypoxia and completely inhibited by 10 μM 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of sGC. sGC abundance (in ng sGC/mg protein) measured via Western immunoblots was ∼10-fold greater in fetal (17.6 ± 1.6) than adult (1.7 ± 0.3) arteries but was not affected by chronic hypoxia. The specific activity of sGC (in pmol cGMP·μg sGC−1·min−1) was similar in fetal (255 ± 64) and adult (280 ± 75) arteries and was inhibited by chronic hypoxia in both fetal (120 ± 10) and adult (132 ± 26) arteries. Rates of cGMP degradation (in pmol cGMP·mg protein−1·min−1) were similar in fetal (159 ± 59) and adult (134 ± 36) arteries but were not significantly depressed by chronic hypoxia in either fetal (115 ± 25) or adult (108 ± 25) arteries. The cGMP analog 8-( p-chlorophenylthio)-cGMP was a more potent vasorelaxant in fetal (pD2 = 4.7 ± 0.1) than adult (pD2 = 4.3 ± 0.1) arteries, but its ability to promote vasodilatation was not affected by chronic hypoxia in either age group. Together, these results reveal that hypoxic inhibition of NO-induced vasodilatation is attributable largely to attenuation of the specific activity of sGC and does not involve significant changes in sGC abundance, cGMP-phosphodiesterase activity, or the vasorelaxant activity of protein kinase G.

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