Antenatal maternal hypoxic stress: Adaptations of the placental renin-angiotensin system in the mouse

Goyal, Ravi; Lister, Rolanda; Leitzke, Arthur; Goyal, Dipali; Gheorghe, Ciprian P.; Longo, Lawrence D.

doi:10.1016/j.placenta.2010.11.004

Cited by 47 publications

(43 citation statements)

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“…Regarding fetal lung, this study corroborated previous evidences concerning ACE, AT 1 and AT 2 expression (13)(14)(15)28). For the first time, the present study showed that renin and angiotensinogen are also expressed during lung development.…”

Section: Discussionsupporting

confidence: 91%

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Local Fetal Lung Renin-Angiotensin System as a Target to Treat Congenital Diaphragmatic Hernia

Nogueira‐Silva

Carvalho-Dias

Piairo

et al. 2011

Mol Med

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Antenatal stimulation of lung growth is a reasonable approach to treat congenital diaphragmatic hernia (CDH), a disease characterized by pulmonary hypoplasia and hypertension. Several evidences from the literature demonstrated a possible involvement of renin-angiotensin system (RAS) during fetal lung development. Thus, the expression pattern of renin, angiotensin-converting enzyme, angiotensinogen, type 1 (AT 1 ) and type 2 (AT 2 ) receptors of angiotensin II (ANGII) was assessed by immunohistochemistry throughout gestation, whereas the function of RAS in the fetal lung was evaluated using fetal rat lung explants. These were morphometrically analyzed and intracellular pathway alterations assessed by Western blot. In nitrofen-induced CDH model, pregnant rats were treated with saline or PD-123319. In pups, lung growth, protein/DNA ratio, radial saccular count, epithelial differentiation and lung maturation, vascular morphometry, right ventricular hypertrophy and overload molecular markers, gasometry and survival time were evaluated. Results demonstrated that all RAS components were constitutively expressed in the lung during gestation and that ANGII had a stimulatory effect on lung branching, mediated by AT 1 receptor, through p44/42 and Akt phosphorylation. This stimulatory effect on lung growth was mimicked by AT 2 -antagonist (PD-123319) treatment. In vivo antenatal PD-123319 treatment increased lung growth, ameliorated indirect parameters of pulmonary hypertension, improved lung function and survival time in nonventilated CDH pups, without maternal or fetal deleterious effects. Therefore, this study demonstrated a local and physiologically active RAS during lung morphogenesis. Moreover, selective inhibition of AT 2 receptor is presented as a putative antenatal therapy for CDH.

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Section: Discussionsupporting

confidence: 91%

“…Regarding lung morphogenesis, there is some evidence that lung expresses ACE as well as AT 1 and AT 2 receptors during fetal development (13)(14)(15). However, RAS components expression pattern, as well as effects during lung morphogenesis, is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Local Fetal Lung Renin-Angiotensin System as a Target to Treat Congenital Diaphragmatic Hernia

Nogueira‐Silva

Carvalho-Dias

Piairo

et al. 2011

Mol Med

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“…One specific mechanism may involve microRNAs (miRNAs), which function to downregulate protein expression without degrading the mRNA. In this regard, reduced expression of the miRNAs that putatively increase translation of ACE2 is observed in fetal lung (32). Thus, posttranscriptional epigenetic programming to increase protein translation may account for discrepancies in the pulmonary mRNA and protein levels observed in the present study.…”

Section: Ontogeny Of Ace2mentioning

confidence: 54%

Ontogeny of angiotensin-converting enzyme 2

2011

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INTRODUCTION:This study examined the temporal expression of angiotensin (ang)-converting enzyme 2 (ace2) during renal, heart, lung, and brain organogenesis in the mouse. RESULTS: We demonstrate that kidney ace2 mRNa levels are low on embryonic day (e) 12.5, increase fourfold during development, and decline in adulthood. In extrarenal tissues, ace2 mRNa levels are also low during early gestation, increase in perinatal period, and peak in adulthood. The lung shows the highest age-related increase in ace2 mRNa levels followed by the brain, kidney, and heart. ace2 protein levels and enzymatic activity are high in all organs studied during gestation and decline postnatally. ang II decreases ace2 mRNa levels and enzymatic activity in kidneys grown ex vivo. These effects of ang II are blocked by the specific ang II aT 1 receptor (aT 1 R) antagonist candesartan, but not by the aT 2 receptor (aT 2 R) antagonist PD123319. DISCUSSION: We conclude that ACE2 gene and protein expression and enzymatic activity are developmentally regulated in a tissue-specific manner. ang II, acting through aT 1 R, exerts a negative feedback on ace2 during kidney development. We postulate that relatively high ace2 protein levels and enzymatic activity observed during gestation may play a role in kidney, lung, brain, and heart organogenesis.

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“…Another possibility is that changes in expression of the angiotensin (AT) type 2 (AT 2 ) receptor can accentuate the potency of bradykinin (7,92). Indeed, in the mouse lung, AT 2 receptor mRNA expression increases following antenatal hypoxia, while AT 1 receptor expression remains stable (34). This finding mirrors the protein expression changes with ontogeny, where AT 2 receptor expression increases from the neonatal mouse to the adult, while AT 1 receptor expression is steady (25).…”

Section: Discussionmentioning

confidence: 98%

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Blum-Johnston

Thorpe

Wee

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of largeconductance Ca 2ϩ -activated K ϩ (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca 2ϩ . Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCa channels during bradykinin-induced vasorelaxation by examining endothelial Ca 2ϩ signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (ϳ140 days gestation) and newborn, 10-to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for Ͼ100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca 2ϩ responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 M nitro-L-arginine methyl ester or 10 M 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2 pathways. BKCa channel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCa channel ␣1-subunit expression but increased ␤1-subunit expression. These results suggest that CH amplifies the contribution of BKCa channels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes. potassium channels; sheep; pulmonary artery; contractility; maturation; hypoxia REGULATION OF SMOOTH MUSCLE tone in pulmonary arteries during development is a delicate balance of vasoconstrictive and vasorelaxant pathways. Endothelial cells play a crucial role in determining the overall level of vasorelaxation (39, 67), and endothelium-dependent relaxation is partially mediated through bradykinin stimulation (31). Bradykinin is a potent vasodilator that is important in the fetal pulmonary circulation, as well as during inflammation, and its relationship to pulmonary hypertension has been explored (5, 31, 83).Endothelial bradykinin receptor activation induces vasorelaxation through modulation of several different intracellular signaling pathways that are largely dependent on a rise of endothelial intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (67). The most widely studied pathway is bradykinin-induced activation of endothelial nitric oxide (NO) synthase (eNOS), an enzyme that generates NO (64). NO acts on nearby smooth muscle cells to cause downstream stimulation of soluble guanylate cyclase (sGC) pathways that leads to vasorelaxation (3,45). Previous studies have shown that regulatio...

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Antenatal maternal hypoxic stress: Adaptations of the placental renin-angiotensin system in the mouse

Cited by 47 publications

References 50 publications

Local Fetal Lung Renin-Angiotensin System as a Target to Treat Congenital Diaphragmatic Hernia

Local Fetal Lung Renin-Angiotensin System as a Target to Treat Congenital Diaphragmatic Hernia

Ontogeny of angiotensin-converting enzyme 2

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

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