In utero hypoxia altered Ang II-induced contraction via PKCβ in fetal cerebral arteries

in Journal of Endocrinology
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  • 1 Institute for Fetology, First Hospital of Soochow University, Suzhou, Jiangsu, China
  • 2 Department of Obstetrics and Gynecology, First Hospital of Soochow University, Suzhou, Jiangsu, China

Correspondence should be addressed to J Tang or Z Xu: tangjiaqi75@163.com or xuzhice@suda.edu.cn

*(H Su, X Chen and Y Zhang contributed equally to this work)

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Cerebral circulation is important in fetal brain development, and angiotensin II (Ang II) plays vital roles in regulation of adult cerebral circulation. However, functions of Ang II in fetal cerebral vasculature and influences of in utero hypoxia on Ang II-mediated fetal cerebral vascular responses are largely unknown. This study investigated the effects and mechanisms of in utero hypoxia on fetal middle cerebral arteries (MCA) via Ang II. Near-term ovine fetuses were exposed to in utero hypoxia, and fetal MCA responses to Ang II were tested for vascular tension, calcium transient, and molecular analysis. Ang II caused significant dose-dependent contraction in control fetal MCA. Ang II-induced MCA constriction was decreased significantly in hypoxic fetuses. Neither losartan (AT1R antagonist, 10−5 mol/L) nor PD123,319 (AT2R antagonist, 10−5 mol/L) altered Ang II-mediated contraction in fetal MCA. Phenylephrine-mediated constriction was also significantly weaker in hypoxic fetuses. Bay K8644 caused similar contractions between the two groups. Protein expression of L-type voltage-dependent calcium channels was unchanged. There were no differences in caffeine-mediated vascular tension or calcium transients. Contraction induced by PDBu (PKC agonist) was obviously weaker in hypoxic MCA. Protein expression of PKCβ was reduced in the hypoxic compared with the control, along with no differences in phosphorylation levels. The results showed that fetal MCA was functionally responsive to Ang II near term. Intrauterine hypoxia reduced the vascular agonist-mediated contraction in fetal MCA, probably via decreasing PKCβ and its phosphorylation, which might play protective effects on fetal cerebral circulation against transient hypoxia.

 

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  • Castillo-Melendez M, Yawno T, Allison BJ, Jenkin G, Wallace EM & Miller SL 2015 Cerebrovascular adaptations to chronic hypoxia in the growth restricted lamb. International Journal of Developmental Neuroscience 5565. (https://doi.org/10.1016/j.ijdevneu.2015.01.004)

    • Search Google Scholar
    • Export Citation
  • Castillo-Melendez M, Yawno T, Sutherland A, Jenkin G, Wallace EM & Miller SL 2017 Effects of antenatal melatonin treatment on the cerebral vasculature in an ovine model of fetal growth restriction. Developmental Neuroscience 323337. (https://doi.org/10.1159/000471797)

    • Search Google Scholar
    • Export Citation
  • Chen Z, Wang G, Zhai X, Hu Y, Gao D, Ma L, Yao J & Tian X 2014 Selective inhibition of protein kinase C beta2 attenuates the adaptor P66 Shc-mediated intestinal ischemia-reperfusion injury. Cell Death and Disease e1164. (https://doi.org/10.1038/cddis.2014.131)

    • Search Google Scholar
    • Export Citation
  • Czikk MJ, Totten S, Hammond R & Richardson BS 2015 Microtubule-associated protein 2 and synaptophysin in the preterm and near-term ovine fetal brain and the effect of intermittent umbilical cord occlusion. Reproductive Sciences 367376. (https://doi.org/10.1177/1933719114529371)

    • Search Google Scholar
    • Export Citation
  • El-Yazbi AF, Abd-Elrahman KS & Moreno-Dominguez A 2015 PKC-mediated cerebral vasoconstriction: role of myosin light chain phosphorylation versus actin cytoskeleton reorganization. Biochemical Pharmacology 263278. (https://doi.org/10.1016/j.bcp.2015.04.011)

    • Search Google Scholar
    • Export Citation
  • Fujita T, Asai T, Andrassy M, Stern DM, Pinsky DJ, Zou YS, Okada M, Naka Y, Schmidt AM & Yan SF 2004 PKCbeta regulates ischemia/reperfusion injury in the lung. Journal of Clinical Investigation 16151623. (https://doi.org/10.1172/JCI19225)

    • Search Google Scholar
    • Export Citation
  • Gao Q, Tang J, Li N, Zhou X, Li Y, Liu Y, Wu J, Yang Y, Shi R, He A, 2017 A novel mechanism of angiotensin II-regulated placental vascular tone in the development of hypertension in preeclampsia. Oncotarget 3073430741. (https://doi.org/10.18632/oncotarget.15416)

    • Search Google Scholar
    • Export Citation
  • Gao Q, Tang J, Li N, Liu B, Zhang M, Sun M & Xu Z 2018 What is precise pathophysiology in development of hypertension in pregnancy? Precision medicine requires precise physiology and pathophysiology. Drug Discovery Today 286299. (https://doi.org/10.1016/j.drudis.2017.10.021)

    • Search Google Scholar
    • Export Citation
  • Gardner DS, Fletcher AJ, Fowden AL & Giussani DA 2001 A novel method for controlled and reversible long term compression of the umbilical cord in fetal sheep. Journal of Physiology 217229. (https://doi.org/10.1111/j.1469-7793.2001.00217.x)

    • Search Google Scholar
    • Export Citation
  • Goyal R, Mittal A, Chu N, Shi L, Zhang L & Longo LD 2009 Maturation and the role of PKC-mediated contractility in ovine cerebral arteries. American Journal of Physiology: Heart and Circulatory Physiology H2242H2252. (https://doi.org/10.1152/ajpheart.00681.2009)

    • Search Google Scholar
    • Export Citation
  • Goyal R, Mittal A, Chu N, Arthur RA, Zhang L & Longo LD 2010 Maturation and long-term hypoxia-induced acclimatization responses in PKC-mediated signaling pathways in ovine cerebral arterial contractility. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology R1377R1386. (https://doi.org/10.1152/ajpregu.00344.2010)

    • Search Google Scholar
    • Export Citation
  • Hagberg H, David Edwards A & Groenendaal F 2016 Perinatal brain damage: the term infant. Neurobiology of Disease 102112. (https://doi.org/10.1016/j.nbd.2015.09.011)

    • Search Google Scholar
    • Export Citation
  • Henrion D, Kubis N & Levy BI 2001 Physiological and pathophysiological functions of the AT(2) subtype receptor of angiotensin II: from large arteries to the microcirculation. Hypertension 11501157. (https://doi.org/10.1161/hy1101.096109)

    • Search Google Scholar
    • Export Citation
  • Hu Y, Tao X, Han X, Xu L, Yin L, Qi Y, Zhao Y, Xu Y, Wang C & Peng J 2016 Dioscin attenuates gastric ischemia/reperfusion injury through the down-regulation of PKC/ERK1/2 signaling via PKCalpha and PKCbeta2 inhibition. Chemico-Biological Interactions 234244. (https://doi.org/10.1016/j.cbi.2016.09.014)

    • Search Google Scholar
    • Export Citation
  • Iwamoto HS, Stucky E & Roman CM 1991 Effect of graded umbilical cord compression in fetal sheep at 0.6–0.7 gestation. American Journal of Physiology H1268H1274. (https://doi.org/10.1152/ajpheart.1991.261.4.H1268)

    • Search Google Scholar
    • Export Citation
  • Kaneko M, White S, Homan J & Richardson B 2003 Cerebral blood flow and metabolism in relation to electrocortical activity with severe umbilical cord occlusion in the near-term ovine fetus. American Journal of Obstetrics and Gynecology 961972. (https://doi.org/10.1067/mob.2003.219)

    • Search Google Scholar
    • Export Citation
  • Kurinczuk JJ, White-Koning M & Badawi N 2010 Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Human Development 329338. (https://doi.org/10.1016/j.earlhumdev.2010.05.010)

    • Search Google Scholar
    • Export Citation
  • Li B, Concepcion K, Meng X & Zhang L 2017 Brain-immune interactions in perinatal hypoxic-ischemic brain injury. Progress in Neurobiology 5068. (https://doi.org/10.1016/j.pneurobio.2017.10.006)

    • Search Google Scholar
    • Export Citation
  • Liu Y, Jin J, Qiao S, Lei S, Liao S, Ge ZD, Li H, Wong GT, Irwin MG & Xia Z 2015 Inhibition of PKCbeta2 overexpression ameliorates myocardial ischaemia/reperfusion injury in diabetic rats via restoring caveolin-3/Akt signaling. Clinical Science 331344. (https://doi.org/10.1042/CS20140789)

    • Search Google Scholar
    • Export Citation
  • Liu Y, Qi L, Wu J, Xu T, Yang C, Chen X, Lv J & Xu Z 2018 Prenatal high-salt diet impaired vasodilatation with reprogrammed renin-angiotensin system in offspring rats. Journal of Hypertension 23692379. (https://doi.org/10.1097/HJH.0000000000001865)

    • Search Google Scholar
    • Export Citation
  • Longo LD, Hull AD, Long DM & Pearce WJ 1993 Cerebrovascular adaptations to high-altitude hypoxemia in fetal and adult sheep. American Journal of Physiology R65R72. (https://doi.org/10.1152/ajpregu.1993.264.1.R65)

    • Search Google Scholar
    • Export Citation
  • Montezano AC, Nguyen Dinh Cat A, Rios FJ & Touyz RM 2014 Angiotensin II and vascular injury. Current Hypertension Reports 431. (https://doi.org/10.1007/s11906-014-0431-2)

    • Search Google Scholar
    • Export Citation
  • Nishigori H, Mazzuca DM, Nygard KL, Han VK & Richardson BS 2008 BDNF and TrkB in the preterm and near-term ovine fetal brain and the effect of intermittent umbilical cord occlusion. Reproductive Sciences 895905. (https://doi.org/10.1177/1933719108324135)

    • Search Google Scholar
    • Export Citation
  • Paulson OB, Waldemar G, Andersen AR, Barry DI, Pedersen EV, Schmidt JF & Vorstrup S 1988 Role of angiotensin in autoregulation of cerebral blood flow. Circulation I55I58.

    • Search Google Scholar
    • Export Citation
  • Pires PW, Dams Ramos CM, Matin N & Dorrance AM 2013 The effects of hypertension on the cerebral circulation. American Journal of Physiology: Heart and Circulatory Physiology H1598H1614. (https://doi.org/10.1152/ajpheart.00490.2012)

    • Search Google Scholar
    • Export Citation
  • Pourmahram GE, Snetkov VA, Shaifta Y, Drndarski S, Knock GA, Aaronson PI & Ward JP 2008 Constriction of pulmonary artery by peroxide: role of Ca2+ release and PKC. Free Radical Biology and Medicine 14681476. (https://doi.org/10.1016/j.freeradbiomed.2008.08.020)

    • Search Google Scholar
    • Export Citation
  • Richardson BS, Carmichael L, Homan J, Johnston L & Gagnon R 1996 Fetal cerebral, circulatory, and metabolic responses during heart rate decelerations with umbilical cord compression. American Journal of Obstetrics and Gynecology 929936. (https://doi.org/10.1016/s0002-9378(96)80027-5)

    • Search Google Scholar
    • Export Citation
  • Ringvold HC & Khalil RA 2017 Protein kinase C as regulator of vascular smooth muscle function and potential target in vascular disorders. Advances in Pharmacology 203301. (https://doi.org/10.1016/bs.apha.2016.06.002)

    • Search Google Scholar
    • Export Citation
  • Shi L, Mao C, Thornton SN, Sun W, Wu J, Yao J & Xu Z 2005 Effects of intracerebroventricular losartan on angiotensin II-mediated pressor responses and c-fos expression in near-term ovine fetus. Journal of Comparative Neurology 571579. (https://doi.org/10.1002/cne.20802)

    • Search Google Scholar
    • Export Citation
  • Silpanisong J, Kim D, Williams JM, Adeoye OO, Thorpe RB & Pearce WJ 2017 Chronic hypoxia alters fetal cerebrovascular responses to endothelin-1. American Journal of Physiology: Cell Physiology C207C218. (https://doi.org/10.1152/ajpcell.00241.2016)

    • Search Google Scholar
    • Export Citation
  • Takeishi Y, Jalili T, Ball NA & Walsh RA 1999 Responses of cardiac protein kinase C isoforms to distinct pathological stimuli are differentially regulated. Circulation Research 264271. (https://doi.org/10.1161/01.res.85.3.264)

    • Search Google Scholar
    • Export Citation
  • Tang J, Li N, Chen X, Gao Q, Zhou X, Zhang Y, Liu B, Sun M & Xu Z 2017 Prenatal hypoxia induced dysfunction in cerebral arteries of offspring rats. Journal of the American Heart Association e006630. (https://doi.org/10.1161/JAHA.117.006630)

    • Search Google Scholar
    • Export Citation
  • Thorpe RB, Hubbell MC, Silpanisong J, Williams JM & Pearce WJ 2017 Chronic hypoxia attenuates the vasodilator efficacy of protein kinase G in fetal and adult ovine cerebral arteries. American Journal of Physiology: Heart and Circulatory Physiology H207H219. (https://doi.org/10.1152/ajpheart.00480.2016)

    • Search Google Scholar
    • Export Citation
  • Williams JM & Pearce WJ 2006 Age-dependent modulation of endothelium-dependent vasodilatation by chronic hypoxia in ovine cranial arteries. Journal of Applied Physiology 225232. (https://doi.org/10.1152/japplphysiol.00221.2005)

    • Search Google Scholar
    • Export Citation
  • Wu C, Li J, Bo L, Gao Q, Zhu Z, Li D, Li S, Sun M, Mao C & Xu Z 2014 High-sucrose diets in pregnancy alter angiotensin II-mediated pressor response and microvessel tone via the PKC/Cav1.2 pathway in rat offspring. Hypertension Research 818823. (https://doi.org/10.1038/hr.2014.94)

    • Search Google Scholar
    • Export Citation
  • Xiao D, Xu Z, Huang X, Longo LD, Yang S & Zhang L 2008 Prenatal gender-related nicotine exposure increases blood pressure response to angiotensin II in adult offspring. Hypertension 12391247. (https://doi.org/10.1161/HYPERTENSIONAHA.107.106203)

    • Search Google Scholar
    • Export Citation
  • Xu Z, Wu Y, Zhang Y, Zhang H & Shi L 2019 Melatonin activates BKCa channels in cerebral artery myocytes via both direct and MT receptor/PKC-mediated pathway. European Journal of Pharmacology 177188. (https://doi.org/10.1016/j.ejphar.2018.10.032)

    • Search Google Scholar
    • Export Citation
  • Zhang Y, Su W, Zhang Q, Xu J, Liu H, Luo J, Zhan L, Xia Z & Lei S 2018 Glycine protects H9C2 cardiomyocytes from high glucose- and hypoxia/reoxygenation-induced injury via inhibiting PKCbeta2 activation and improving mitochondrial quality. Journal of Diabetes Research 9502895. (https://doi.org/10.1155/2018/9502895)

    • Search Google Scholar
    • Export Citation
  • Zhao Y, Long W, Zhang L & Longo LD 2003 Extracellular signal-regulated kinases and contractile responses in ovine adult and fetal cerebral arteries. Journal of Physiology 691703. (https://doi.org/10.1113/jphysiol.2003.046128)

    • Search Google Scholar
    • Export Citation