Muscarinic receptor M1 and phosphodiesterase 1 are key determinants in pulmonary vascular dysfunction following perinatal hypoxia in mice

2008 ◽  
Vol 295 (1) ◽  
pp. L201-L213 ◽  
Author(s):  
Anne-Christine Peyter ◽  
Vincent Muehlethaler ◽  
Lucas Liaudet ◽  
Mathieu Marino ◽  
Stefano Di Bernardo ◽  
...  
Keyword(s):  
Muscarinic Receptor ◽  
Vascular Dysfunction ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Vascular Diseases ◽  
Perinatal Hypoxia ◽  
Long Term Effects ◽  
Calcium Dependent ◽  
Increased Sensitivity ◽  
Endothelium Dependent Relaxation

Perinatal adverse events such as limitation of nutrients or oxygen supply are associated with the occurrence of diseases in adulthood, like cardiovascular diseases and diabetes. We investigated the long-term effects of perinatal hypoxia on the lung circulation, with particular attention to the nitric oxide (NO)/cGMP pathway. Mice were placed under hypoxia in utero 5 days before delivery and for 5 days after birth. Pups were then bred in normoxia until adulthood. Adults born in hypoxia displayed an altered regulation of pulmonary vascular tone with higher right ventricular pressure in normoxia and increased sensitivity to acute hypoxia compared with controls. Perinatal hypoxia dramatically decreased endothelium-dependent relaxation induced by ACh in adult pulmonary arteries (PAs) but did not influence NO-mediated endothelium-independent relaxation. The M3 muscarinic receptor was implicated in the relaxing action of ACh and M1 muscarinic receptor (M1AChR) in its vasoconstrictive effects. Pirenzepine or telenzepine, two preferential inhibitors of M1AChR, abolished the adverse effects of perinatal hypoxia on ACh-induced relaxation. M1AChR mRNA expression was increased in lungs and PAs of mice born in hypoxia. The phosphodiesterase 1 (PDE1) inhibitor vinpocetine also reversed the decrease in ACh-induced relaxation following perinatal hypoxia, suggesting that M1AChR-mediated alteration of ACh-induced relaxation is due to the activation of calcium-dependent PDE1. Therefore, perinatal hypoxia leads to an altered pulmonary circulation in adulthood with vascular dysfunction characterized by impaired endothelium-dependent relaxation and M1AChR plays a predominant role. This raises the possibility that muscarinic receptors could be key determinants in pulmonary vascular diseases in relation to “perinatal imprinting.”

scholarly journals Perinatal Nitric Oxide Therapy Prevents Adverse Effects of Perinatal Hypoxia on the Adult Pulmonary Circulation

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Anne-Christine Peyter ◽  
Flavien Delhaes ◽  
Giacomo Diaceri ◽  
Steeve Menétrey ◽  
Jean-François Tolsa
Keyword(s):  
Nitric Oxide ◽  
Adverse Effects ◽  
Pulmonary Circulation ◽  
Pulmonary Arteries ◽  
Hypoxic Exposure ◽  
Perinatal Hypoxia ◽  
Simultaneous Administration ◽  
Long Term Effects ◽  
Beneficial Effects

Adverse events in utero are associated with the occurrence of chronic diseases in adulthood. We previously demonstrated in mice that perinatal hypoxia resulted in altered pulmonary circulation in adulthood, with a decreased endothelium-dependent relaxation of pulmonary arteries, associated with long-term alterations in the nitric oxide (NO)/cyclic GMP pathway. The present study investigated whether inhaled NO (iNO) administered simultaneously to perinatal hypoxia could have potential beneficial effects on the adult pulmonary circulation. Indeed, iNO is the therapy of choice in humans presenting neonatal pulmonary hypertension. Long-term effects of neonatal iNO therapy on adult pulmonary circulation have not yet been investigated. Pregnant mice were placed in hypoxia (13% O2) with simultaneous administration of iNO 5 days before delivery until 5 days after birth. Pups were then raised in normoxia until adulthood. Perinatal iNO administration completely restored acetylcholine-induced relaxation, as well as endothelial nitric oxide synthase protein content, in isolated pulmonary arteries of adult mice born in hypoxia. Right ventricular hypertrophy observed in old mice born in hypoxia compared to controls was also prevented by perinatal iNO treatment. Therefore, simultaneous administration of iNO during perinatal hypoxic exposure seems able to prevent adverse effects of perinatal hypoxia on the adult pulmonary circulation.

Abstract 17112: Transgenic Endothelial-Specific HIV-Nef Expression Induces Pulmonary Hypertension and Systemic Vascular Dysfunction, Which Can Be Reverted by Treatment With Statin

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Natalia Bogatcheva ◽  
Sarvesh Chelvanambi ◽  
Xingjuan Chen ◽  
Alexander Obukhov ◽  
Matthias Clauss
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Dysfunction ◽  
Vascular Diseases ◽  
Arterial Disease ◽  
Statin Treatment ◽  
Systemic Circulation ◽  
Vascular Pathology ◽  
Systemic Hypertension ◽  
Dependent Manner ◽  
Specific Expression

Introduction: HIV patients on ART perplexingly remain at higher risk for developing cardiovascular diseases including acute peripheral arterial disease and pulmonary hypertension. A likely culprit for observed vascular changes is HIV protein Nef, detected both intracellularly and extracellularly in the absence of HIV RNA or DNA. Nef is known to induce endothelial dysfunction through the activation of NADPH; statins are known to inhibit NADPH activation. Hypothesis: Nef expression in endothelial cells will trigger cardiopulmonary and vascular pathology; Nef effects will be reversed by statin. Methods: Endothelial-specific expression of HIV-Nef was achieved by mating the VE-Cadherin-Tet off mice with TRE-Nef mice. The resulting Nef+ double transgenics and their Nef- negative littermates were maintained without doxycycline to induce Nef expression. Changes in pulmonary acceleration and ejection times were analyzed by ultrasound (INVEVO2100). Additionally, we assessed the ability of bradykinin-preconstricted aortic rings to dilate in response to acetylcholine in NO-dependent manner. Results: Between week 10 and week 13 of age, Nef expressing mice displayed gradual reduction of PAT/PET ratio (down to the 75% of the original PAT/PET ratio at week 10), indicative of developing pulmonary hypertension (N=6). PAT/PET ratio in Nef-negative mice did not change significantly between week 10 and 13 of age. Importantly, statin treatment initiated at week 10 completely suppressed PAT/PET changes developing in Nef-expressing mice. Arterial rings from Nef expressing mice (n=4) showed significantly impaired dilatation in response to acetylcholine (10% relaxation in Nef+ mice vs 40% relaxation in Nef-negative littermates, p=0.03), indicative of changes in systemic circulation. This difference was significantly attenuated in Nef+ mice receiving statin treatment. Conclusions: Our data suggests that mice with endothelial expression of HIV-Nef display pathological changes in pulmonary and systemic circulation. Statin treatment significantly attenuates changes in parameters indicative of pulmonary and systemic hypertension, suggesting that statin will be beneficial for patients with HIV-induced cardiopulmonary and vascular diseases.

Acute hypoxia increases intracellular [Ca2+] in pulmonary arterial smooth muscle by enhancing capacitative Ca2+ entry

2005 ◽  
Vol 288 (6) ◽  
pp. L1059-L1069 ◽  
Author(s):  
Jian Wang ◽  
Larissa A. Shimoda ◽  
Letitia Weigand ◽  
Wenqian Wang ◽  
Dejun Sun ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Primary Cultures ◽  
Fluorescent Microscopy ◽  
Pulmonary Arteries ◽  
Arterial Smooth Muscle ◽  
Fura 2 ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

Hypoxic pulmonary vasoconstriction (HPV) requires influx of extracellular Ca2+ in pulmonary arterial smooth muscle cells (PASMCs). To determine whether capacitative Ca2+ entry (CCE) through store-operated Ca2+ channels (SOCCs) contributes to this influx, we used fluorescent microscopy and the Ca2+-sensitive dye fura-2 to measure effects of 4% O2 on intracellular [Ca2+] ([Ca2+]i) and CCE in primary cultures of PASMCs from rat distal pulmonary arteries. In PASMCs perfused with Ca2+-free Krebs Ringer bicarbonate solution (KRBS) containing cyclopiazonic acid to deplete Ca2+ stores in sarcoplasmic reticulum and nifedipine to prevent Ca2+ entry through L-type voltage-operated Ca2+ channels (VOCCs), hypoxia markedly enhanced both the increase in [Ca2+]i caused by restoration of extracellular [Ca2+] and the rate at which extracellular Mn2+ quenched fura-2 fluorescence. These effects, as well as the increased [Ca2+]i caused by hypoxia in PASMCs perfused with normal salt solutions, were blocked by the SOCC antagonists SKF-96365, NiCl2, and LaCl3 at concentrations that inhibited CCE >80% but did not alter [Ca2+]i responses to 60 mM KCl. In contrast, the VOCC antagonist nifedipine inhibited [Ca2+]i responses to hypoxia by only 50% at concentrations that completely blocked responses to KCl. The increased [Ca2+]i caused by hypoxia was completely reversed by perfusion with Ca2+-free KRBS. LaCl3 increased basal [Ca2+]i during normoxia, indicating effects other than inhibition of SOCCs. Our results suggest that acute hypoxia enhances CCE through SOCCs in distal PASMCs, leading to depolarization, secondary activation of VOCCs, and increased [Ca2+]i. SOCCs and CCE may play important roles in HPV.

Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store-operated Ca2+ and nonselective cation channels

2005 ◽  
Vol 289 (1) ◽  
pp. L5-L13 ◽  
Author(s):  
Letitia Weigand ◽  
Joshua Foxson ◽  
Jian Wang ◽  
Larissa A. Shimoda ◽  
J. T. Sylvester
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Cation Channels ◽  
Pulmonary Vasoconstriction ◽  
Nonselective Cation Channels ◽  
Pressor Responses ◽  
Intracellular Ca ◽  
Pulmonary Arterial

Previous studies indicated that acute hypoxia increased intracellular Ca2+ concentration ([Ca2+]i), Ca2+ influx, and capacitative Ca2+ entry (CCE) through store-operated Ca2+ channels (SOCC) in smooth muscle cells from distal pulmonary arteries (PASMC), which are thought to be a major locus of hypoxic pulmonary vasoconstriction (HPV). Moreover, these effects were blocked by Ca2+-free conditions and antagonists of SOCC and nonselective cation channels (NSCC). To test the hypothesis that in vivo HPV requires CCE, we measured the effects of SOCC/NSCC antagonists (SKF-96365, NiCl2, and LaCl3) on pulmonary arterial pressor responses to 2% O2 and high-KCl concentrations in isolated rat lungs. At concentrations that blocked CCE and [Ca2+]i responses to hypoxia in PASMC, SKF-96365 and NiCl2 prevented and reversed HPV but did not alter pressor responses to KCl. At 10 μM, LaCl3 had similar effects, but higher concentrations (30 and 100 μM) caused vasoconstriction during normoxia and potentiated HPV, indicating actions other than SOCC blockade. Ca2+-free perfusate and the voltage-operated Ca2+ channel (VOCC) antagonist nifedipine were potent inhibitors of pressor responses to both hypoxia and KCl. We conclude that HPV required influx of Ca2+ through both SOCC and VOCC. This dual requirement and virtual abolition of HPV by either SOCC or VOCC antagonists suggests that neither channel provided enough Ca2+ on its own to trigger PASMC contraction and/or that during hypoxia, SOCC-dependent depolarization caused secondary activation of VOCC.

Heterogeneity in role of endothelium-derived NO in pulmonary arteries and veins of full-term fetal lambs

1995 ◽  
Vol 268 (4) ◽  
pp. H1586-H1592 ◽  
Author(s):  
Y. Gao ◽  
H. Zhou ◽  
J. U. Raj
Keyword(s):  
Nitric Oxide ◽  
Isometric Force ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Full Term ◽  
Fourth Generation ◽  
Cyclic Monophosphate ◽  
Arteries And Veins ◽  
Endothelium Dependent Relaxation

Endothelium-derived nitric oxide (EDNO) modulates fetal pulmonary vasoactivity. The role of EDNO in regulation of vasomotor tone in fetal pulmonary arteries vs. that in veins is not known. We have investigated the role of EDNO in the responses of pulmonary arteries and veins of full-term fetal lambs. Fourth-generation pulmonary arterial and venous rings were suspended in organ chambers filled with modified Krebs-Ringer bicarbonate solution (95% O2-5% CO2 at 37 degrees C), and their isometric force was measured. N omega-nitro-L-arginine had no effect on the resting tension of pulmonary arteries with endothelium but caused contraction of pulmonary veins with endothelium. The basal level of intracellular guanosine 3',5'-cyclic monophosphate (cGMP) of pulmonary veins with endothelium was higher than that of arteries with endothelium. In pulmonary arteries, bradykinin, but not acetylcholine, induced endothelium-dependent relaxation and an increase in cGMP content. In pulmonary veins, acetylcholine, but not bradykinin, induced endothelium-dependent relaxation and an increase in cGMP content. Agonist-induced maximal relaxation and increases in cGMP content were smaller in pulmonary arteries than in veins. All these endothelium-dependent responses were abolished by N omega-nitro-L-arginine. In tissues without endothelium, nitric oxide induced significantly less relaxation and less increase in cGMP content in pulmonary arteries than in pulmonary veins. All vessels relaxed similarly to 8-bromoguanosine 3',5'-cyclic monophosphate. Our data suggest that the role of EDNO in modulating tone differs between pulmonary arteries and veins in full-term fetal lambs.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Long Term Effects of Neonatal Hypoglycemia on Muscarinic Receptor Function in the Cerebellum

2017 ◽  
Vol 2 (1) ◽  
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Muscarinic Receptor ◽  
Receptor Subtype ◽  
Receptor Function ◽  
Long Term Effects ◽  
Neonatal Hypoglycemia ◽  
Neonatal Stress ◽  
Old Rats

Neonatal stress conditions like hypoglycemia cause brain damage by affecting various signaling pathways thereby causing long term effects on brain functions. A proper understanding of the signaling pathways affected by this stress will help to devise better neonatal care. The focus of the current study was to evaluate the effect of neonatal hypoglycemic insult on cerebellar metabotropic cholinergic receptor function in one month old rats. The receptor analysis of cholinergic muscarinic receptors were done by radioreceptor assays and gene expression was analysed using Real Time PCR. Neonatal hypoglycemia significantly reduced (p<0.001) the cerebellar muscarinic receptor density with a down regulation (p<0.001) of muscarinic M3 receptor subtype gene expression in one month old rats. Both muscarinic M1 and M2 receptor subtype expression were not significantly altered. The catabolic enzyme in acetyl choline metabolism- acetylcholine esterase – showed a significant (p<0.001) up regulation with no siginificant change in the anabolic enzyme – choline acetyl transferase, signifying a change in the turnover ratio. Targeting these pathways at different levels can be exploited to devise better treatment for neonatal stress management and also for diseases with impaired insulin secretion such as diabetes.

scholarly journals Protection of the vascular endothelium in experimental situations

2011 ◽  
Vol 4 (1) ◽  
pp. 20-26 ◽  
Author(s):  
Ružena Sotníková ◽  
Jana Nedelčevová ◽  
Jana Navarová ◽  
Viera Nosáľová ◽  
Katarína Drábiková ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vascular Endothelium ◽  
Vascular Dysfunction ◽  
Antioxidant Properties ◽  
Pharmacological Intervention ◽  
Ros Production ◽  
Nitric Oxide Radical ◽  
Endothelium Dependent Relaxation

Protection of the vascular endothelium in experimental situationsOne of the factors proposed as mediators of vascular dysfunction observed in diabetes is the increased generation of reactive oxygen species (ROS). This provides support for the use of antioxidants as early and appropriate pharmacological intervention in the development of late diabetic complications. In streptozotocin (STZ)-induced diabetes in rats we observed endothelial dysfuction manifested by reduced endothelium-dependent response to acetylcholine of the superior mesenteric artery (SMA) and aorta, as well as by increased endothelaemia. Changes in endothelium-dependent relaxation of SMA were induced by injury of the nitric oxide radical (·NO)-signalling pathway since the endothelium-derived hyperpolarising factor (EDHF)-component of relaxation was not impaired by diabetes. The endothelial dysfunction was accompanied by decreased ·NO bioavailabity as a consequence of reduced activity of eNOS rather than its reduced expression. The results obtained using the chemiluminiscence method (CL) argue for increased oxidative stress and increased ROS production. The enzyme NAD(P)H-oxidase problably participates in ROS production in the later phases of diabetes. Oxidative stress was also connected with decreased levels of reduced glutathione (GSH) in the early phase of diabetes. After 10 weeks of diabetes, adaptational mechanisms probably took place because GSH levels were not changed compared to controls. Antioxidant properties of SMe1EC2 foundin vitrowere partly confirmedin vivo.Administration of SMe1EC2 protected endothelial function. It significantly decreased endothelaemia of diabetic rats and improved endothelium-dependent relaxation of arteries, slightly decreased ROS-production and increased bioavailability of ·NO in the aorta. Further studies with higher doses of SMe1EC2 may clarify the mechanism of its endothelium-protective effectin vivo.

Abstract 14820: Sirt7 Deficiency in Blood Vessel Components Impairs Vascular Function by Inhibiting Cell Cycle- and Inflammatory-Related Protein Expression

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yuichi Kimura ◽  
Yasuhiro Izumiya ◽  
Satoshi Araki ◽  
Satoru Yamamura ◽  
Yoshiro Onoue ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Blood Flow ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Vascular Diseases ◽  
Tube Formation ◽  
Hindlimb Ischemia ◽  
Proliferation Assay

Introduction: Aging is a well-established cardiovascular risk factor and associated with vascular dysfunction. Sirt7, one of the members of mammalian sirtuin family, is thought to be involved in age-related diseases. However, little is known about the relative contribution of Sirt7 in vascular dysfunction. Hypothesis: Sirt7 maintains vascular cell functions and its deficiency plays a critical role in vascular diseases. Methods: Sirt7 loss- and gain-of-function experiments were performed with human aortic smooth muscle cells (HAoSMCs) and human umbilical vein endothelial cells (HUVECs). In vivo, blood flow recovery was evaluated by hindlimb ischemia model in homozygous Sirt7 deficient (Sirt7-/-) and wild-type (WT) mice. Irradiated WT mice were intravenously received bone marrow (BM) cells from WT or Sirt7 -/- mouse to achieve BM transfer. Results: An RNAi-medicated Sirt7 knockdown resulted in a significant inhibition of HAoSMCs proliferation following serum or Platelet-derived growth factor BB (PDGF-BB) stimulation as determined by cell count, BrdU cell proliferation assay and MTS proliferation assay. Knockdown of endogenous Sirt7 also reduced cell migration as revealed by Boyden chamber migration assay. The Cyclin D1 and Cyclin dependent kinase 2 (CDK2) protein levels were significantly decreased in Sirt7 siRNA-treated HAoSMCs in response to serum or PDGF-BB stimulation. In endothelial cells, knockdown of Sirt7 attenuated tube formation, proliferation and migration. These changes were accompanied by reduced ERK activation and VCAM-1 mRNA and protein expression in Sirt7 siRNA-treated HUVECs. Conversely, overexpression of Sirt7 by adenovirus enhanced tube formation and cell proliferation. In vivo, blood flow recovery in response to hindlimb ischemia was significantly attenuated in Sirt7-/- mice compared with WT mice. There was no difference in blood flow recovery between WT mice transplanted with WT or Sirt7-/- BM cells suggesting that Sirt7 deficiency in vascular cells have a predominant effect on attenuated blood flow recovery in response to hindlimb ischemia. Conclusions: Sirt7 in blood vessel components have an important role in maintenance of vascular function. Sirt7 could be a promising therapeutic target for vascular diseases.

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