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Antenatal Maternal Hypoxic Stress: Adaptations in Fetal Lung Renin-Angiotensin System

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Abstract

Antenatal maternal hypoxia (AMH) can lead to intrauterine growth restriction (IUGR), as well as idiopathic pulmonary hypertension of newborn and adult, the latter of which may be a consequence of alterations in the local pulmonary renin-angiotensin system (RAS). Little is known of these adaptations, however. Thus, we tested the hypothesis that antenatal maternal hypoxia is associated with alterations in gene and protein expression of the pulmonary renin-angiotensin system, which may play an important role in pulmonary disorders in the offspring. In FVB/NJ mice, we studied messenger RNA (mRNA) and protein expression, as well as promoter DNA methylation and microRNA (miRNA) levels in response to 48 hours hypoxia (10.5% O2) at 15.5 day post coitum (DPC). In response to AMH, the pulmonary mRNA levels of angiotensin-converting enzyme (ACE) 1.2, ACE-2, and angiotensin II type 1b (AT-1b) receptors were increased significantly, as compared to controls (N = 4). In response to antenatal hypoxia, pulmonary protein levels of renin and ACE-2 also were increased significantly, whereas ACE-1 protein expression was reduced. In fetal lungs, we also observed reduced expression of the miRNAs: mmu-mir −199b, −27b, −200b, and −468 that putatively increase the translation of renin, ACE-1, ACE-2, and AT-1 receptors, respectively. In response to AMH, promoter methylation of ACE was unchanged. We conclude that AMH leads to changes in expression of pulmonary RAS of fetal mice. The possible implications of these changes for the regulation of pulmonary vascular contractility in later life remain to be explored.

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References

  1. Williams SJ, Campbell ME, McMillen IC, Davidge ST. Differential effects of maternal hypoxia or nutrient restriction on carotid and femoral vascular function in neonatal rats. Am J Physiol Regul Integr Comp Physiol. 2005;288(2):R360–R367.

    Article  CAS  PubMed  Google Scholar 

  2. Golan H, Kashtutsky I, Hallak M, Sorokin Y, Huleihel M. Maternal hypoxia during pregnancy delays the development of motor reflexes in newborn mice. Dev Neurosci. 2004;26(1):24–29.

    Article  CAS  PubMed  Google Scholar 

  3. Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Mitchell AA. Risk factors for persistent pulmonary hypertension of the newborn. Pediatrics. 2007;120(2):e272–e282.

    Article  PubMed  Google Scholar 

  4. Wang Z, Huang Z, Lu G, Lin L, Ferrari M. Hypoxia during pregnancy in rats leads to early morphological changes of atherosclerosis in adult offspring. Am J Physiol Heart Circ Physiol. 2009;296(5):H1321–H1328.

    Article  CAS  PubMed  Google Scholar 

  5. Regnault TR, de Vrijer B, Galan HL, Wilkening RB, Battaglia FC, Meschia G. Development and mechanisms of fetal hypoxia in severe fetal growth restriction. Placenta. 2007;28(7):714–723.

    Article  CAS  PubMed  Google Scholar 

  6. Gheorghe CP, Goyal R, Holweger JD, Longo LD. Placental gene expression responses to maternal protein restriction in the mouse. Placenta. 2009;30(5):411–417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gao Y, Portugal AD, Negash S, Zhou W, Longo LD, Usha Raj J. Role of Rho kinases in PKG-mediated relaxation of pulmonary arteries of fetal lambs exposed to chronic high altitude hypoxia. Am J Physiol Lung Cell Mol Physiol. 2007;292(3):L678–L684.

    Article  CAS  PubMed  Google Scholar 

  8. Fleming I, Kohlstedt K, Busse R. The tissue renin-angiotensin system and intracellular signalling. Curr Opin Nephrol Hypertens. 2006;15(1):8–13.

    Article  CAS  PubMed  Google Scholar 

  9. Valencia JC, Pacheco-Rodriguez G, Carmona AK, et al. Tissue-specific renin-angiotensin system in pulmonary lymphangioleiomyomatosis. Am J Respir Cell Mol Biol. 2006;35(1):40–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Goyal R, Galffy A, Field SA, Gheorghe CP, Mittal A, Longo LD. Maternal protein deprivation: changes in systemic renin-angiotensin system of the mouse fetus. Reprod Sci. 2009;16(9):894–904.

    Article  CAS  PubMed  Google Scholar 

  11. Goyal R, Goyal D, Leitzke A, Gheorghe CP, Longo LD. Brain renin-angiotensin system: fetal epigenetic programming by maternal protein restriction during pregnancy. Reprod Sci. 2010;17(3):227–238.

    Article  PubMed  CAS  Google Scholar 

  12. Goyal R, Yellon SM, Longo LD, Mata-Greenwood E. Placental gene expression in a rat “model” of placental insufficiency. Placenta. 2010;31(7):568–575.

    Article  CAS  PubMed  Google Scholar 

  13. Mascitelli L, Pezzetta F. Inhibition of the renin-angiotensin system in patients with COPD and pulmonary hypertension. Chest. 2007;131(3):938; author reply 938-939.

    Article  PubMed  Google Scholar 

  14. Nong Z, Stassen JM, Moons L, Collen D, Janssens S. Inhibition of tissue angiotensin-converting enzyme with quinapril reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling. Circulation. 1996;94(8):1941–1947.

    Article  CAS  PubMed  Google Scholar 

  15. Wood CE, Kane C, Raff H. Peripheral chemoreceptor control of fetal renin responses to hypoxia and hypercapnia. Circ Res. 1990;67(3):722–732.

    Article  CAS  PubMed  Google Scholar 

  16. Gheorghe CP, Mohan S, Oberg KC, Longo LD. Gene expression patterns in the hypoxic murine placenta: a role in epigenesis?. Reprod Sci. 2007;14(3):223–233.

    Article  CAS  PubMed  Google Scholar 

  17. Downs KM, Davies T. Staging of gastrulating mouse embryos by morphological landmarks in the dissecting microscope. Development. 1993;118(4):1255–1266.

    CAS  PubMed  Google Scholar 

  18. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):e45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhao Y, Long W, Zhang L, Longo LD. Extracellular signal-regulated kinases and contractile responses in ovine adult and fetal cerebral arteries. J Physiol. 2003;551(pt 2):691–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Frommer M, McDonald LE, Millar DS, et al. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci U S A. 1992;89(5):1827–1831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kumaki Y, Oda M, Okano M. QUMA: quantification tool for methylation analysis. Nucleic Acids Res. 2008;36:W170–W175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007;27(1):91–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Grady EF, Sechi LA, Griffin CA, Schambelan M, Kalinyak JE. Expression of AT2 receptors in the developing rat fetus. J Clin Invest. 1991;88(3):921–933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Campbell DJ, Habener JF. Angiotensinogen gene is expressed and differentially regulated in multiple tissues of the rat. J Clin Invest. 1986;78(1):31–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Entzeroth M, Hadamovsky S. Angiotensin II receptors in the rat lung are of the AII-1 subtype. Eur J Pharmacol. 1991;206(3):237–241.

    Article  CAS  PubMed  Google Scholar 

  26. Cassis L, Shenoy U, Lipke D, Baughn J, Fettinger M, Gillespie M. Lung angiotensin receptor binding characteristics during the development of monocrotaline-induced pulmonary hypertension. Biochem Pharmacol. 1997;54(1):27–31.

    Article  CAS  PubMed  Google Scholar 

  27. Phillips MI, Speakman EA, Kimura B. Levels of angiotensin and molecular biology of the tissue renin angiotensin systems. Regul Pept. 1993;43(1–2):1–20.

    Article  CAS  PubMed  Google Scholar 

  28. Marshall RP. The pulmonary renin-angiotensin system. Curr Pharm Des. 2003;9(9):715–722.

    Article  CAS  PubMed  Google Scholar 

  29. Roy SN, Kusari J, Soffer RL, Lai CY, Sen GC. Isolation of cDNA clones of rabbit angiotensin converting enzyme: identification of two distinct mRNAs for the pulmonary and the testicular isozymes. Biochem Biophys Res Commun. 1988;155(2):678–684.

    Article  CAS  PubMed  Google Scholar 

  30. Bernstein KE, Martin BM, Bernstein EA, Linton J, Striker L, Striker G. The isolation of angiotensin-converting enzyme cDNA. J Biol Chem. 1988;263(23):11021–11024.

    CAS  PubMed  Google Scholar 

  31. Pasquinelli AE, Ruvkun G. Control of developmental timing by micrornas and their targets. Annu Rev Cell Dev Biol. 2002;18:495–513.

    Article  CAS  PubMed  Google Scholar 

  32. Wallace KB, Bailie MD, Hook JB. Angiotensin-converting enzyme in developing lung and kidney. Am J Physiol. 1978;234(3):R141–R145.

    CAS  PubMed  Google Scholar 

  33. Wallace KB, Bailie MD, Hook JB. Development of angiotensin-converting enzyme in fetal rat lungs. Am J Physiol. 1979;236(1):R57–R60.

    CAS  PubMed  Google Scholar 

  34. O’Connor SJ, Fowden AL, Holdstock N, Giussani DA, Forhead AJ. Developmental changes in pulmonary and renal angiotensin-converting enzyme concentration in fetal and neonatal horses. Reprod Fertil Dev. 2002;14(7–8):413–417.

    Article  PubMed  Google Scholar 

  35. Ferreira AJ, Santos RA, Almeida AP. Angiotensin-(1-7): cardioprotective effect in myocardial ischemia/reperfusion. Hypertension. 2001;38(3 pt 2):665–668.

    Article  CAS  PubMed  Google Scholar 

  36. Yamazato Y, Ferreira AJ, Hong KH, et al. Prevention of pulmonary hypertension by angiotensin-converting enzyme 2 gene transfer. Hypertension. 2009;54(2):365–371.

    Article  CAS  PubMed  Google Scholar 

  37. Lin KS, Chan JY, Chan SH. Involvement of AT2 receptors at NRVL in tonic baroreflex suppression by endogenous angiotensins. Am J Physiol. 1997;272(5 pt 2):H2204–H2210.

    CAS  PubMed  Google Scholar 

  38. Timmermans PB, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 1993;45:205–251.

    CAS  PubMed  Google Scholar 

  39. Sasamura H, Hein L, Krieger JE, Pratt RE, Kobilka BK, Dzau VJ. Cloning, characterization, and expression of two angiotensin receptor (AT-1) isoforms from the mouse genome. Biochem Biophys Res Commun. 1992;185(1):253–259.

    Article  CAS  PubMed  Google Scholar 

  40. Iwai N, Inagami T. Identification of two subtypes in the rat type I angiotensin II receptor. FEBS Lett. 1992;298(2–3):257–260.

    Article  CAS  PubMed  Google Scholar 

  41. Konishi H, Kuroda S, Inada Y, Fujisawa Y. Novel subtype of human angiotensin II type 1 receptor: cDNA cloning and expression. Biochem Biophys Res Commun. 1994;199(2):467–474.

    Article  CAS  PubMed  Google Scholar 

  42. Davisson RL, Oliverio MI, Coffman TM, Sigmund CD. Divergent functions of angiotensin II receptor isoforms in the brain. J Clin Invest. 2000;106(1):103–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Center for Perinatal Biology, Departments of Physiology, and Obstetrics and Gynecology School of Medicine, Loma Linda University, Loma Linda, CA, 92350, USA

    Ravi Goyal MD, PhD, Arthur Leitzke BS, Dipali Goyal BS, Ciprian P. Gheorghe MD, PhD & Lawrence D. Longo MD

  2. Department of Obstetrics and Gynecology, School of Medicine, Loma Linda University, Loma Linda, CA, USA

    Lawrence D. Longo MD

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  1. Ravi Goyal MD, PhD
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  2. Arthur Leitzke BS
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  3. Dipali Goyal BS
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  4. Ciprian P. Gheorghe MD, PhD
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  5. Lawrence D. Longo MD
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Correspondence to Lawrence D. Longo MD.

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Goyal, R., Leitzke, A., Goyal, D. et al. Antenatal Maternal Hypoxic Stress: Adaptations in Fetal Lung Renin-Angiotensin System. Reprod. Sci. 18, 180–189 (2011). https://doi.org/10.1177/1933719110385134

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