Loss of placental growth factor ameliorates maternal hypertension and preeclampsia in mice

Preeclampsia remains a clinical challenge due to its poorly understood pathogenesis. A prevailing notion is that increased placental production of soluble fms-like tyrosine kinase-1 (sFlt-1) causes the maternal syndrome by inhibiting proangiogenic placental growth factor (PlGF) and VEGF. However, the significance of PlGF suppression in preeclampsia is uncertain. To test whether preeclampsia results from the imbalance of angiogenic factors reflected by an abnormal sFlt-1/PlGF ratio, we studied PlGF KO (Pgf-/-) mice and noted that the mice did not develop signs or sequelae of preeclampsia despite a marked elevation in circulating sFLT-1. Notably, PlGF KO mice had morphologically distinct placentas, showing an accumulation of junctional zone glycogen. We next considered the role of placental PlGF in an established model of preeclampsia (pregnant catechol-O-methyltransferase-deficient [COMT-deficient] mice) by generating mice with deletions in both the Pgf and Comt genes. Deletion of placental PlGF in the context of COMT loss resulted in a reduction in maternal blood pressure and increased placental glycogen, indicating that loss of PlGF might be protective against the development of preeclampsia. These results identify a role for PlGF in placental development and support a complex model for the pathogenesis of preeclampsia beyond an angiogenic factor imbalance

STOX1 deficiency is associated with renin-mediated gestational hypertension and placental defects

The pathogenesis of preeclampsia and other hypertensive disorders of pregnancy remains poorly defined despite the substantial burden of maternal and neonatal morbidity associated with these conditions. In particular, the role of genetic variants as determinants of disease susceptibility is understudied. Storkhead-box protein 1 (STOX1) was first identified as a preeclampsia risk gene through family-based genetic linkage studies in which loss-of-function variants were proposed to underlie increased preeclampsia susceptibility. We generated a genetic Stox1 loss-of-function mouse model (Stox1 KO) to evaluate whether STOX1 regulates blood pressure in pregnancy. Pregnant Stox1-KO mice developed gestational hypertension evidenced by a significant increase in blood pressure compared with WT by E17.5. While severe renal, placental, or fetal growth abnormalities were not observed, the Stox1-KO phenotype was associated with placental vascular and extracellular matrix abnormalities. Mechanistically, we found that gestational hypertension in Stox1-KO mice resulted from activation of the uteroplacental renin-angiotensin system. This mechanism was supported by showing that treatment of pregnant Stox1-KO mice with an angiotensin II receptor blocker rescued the phenotype. Our study demonstrates the utility of genetic mouse models for uncovering links between genetic variants and effector pathways implicated in the pathogenesis of hypertensive disorders of pregnancy

Mouse models for preeclampsia: disruption of redox-regulated signaling

The concept that oxidative stress contributes to the development of human preeclampsia has never been tested in genetically-defined animal models. Homozygous deletion of catechol-Omethyl transferase (Comt-/-) in pregnant mice leads to human preeclampsia-like symptoms (high blood pressure, albuminurea and preterm birth) resulting from extensive vasculo-endothelial pathology, primarily at the utero-fetal interface where maternal cardiac output is dramatically increased during pregnancy. Comt converts estradiol to 2-methoxyestradiol 2 (2ME2) which counters angiogenesis by depleting hypoxia inducible factor-1 alpha (HIF-1 alpha) at late pregnancy. We propose that in wild type (Comt++) pregnant mice, 2ME2 destabilizes HIF-1 alpha by inhibiting mitochondrial superoxide dismutase (MnSOD). Thus, 2ME2 acts as a pro-oxidant, disrupting redox-regulated signaling which blocks angiogenesis in wild type (WT) animals in physiological pregnancy. Further, we suggest that a lack of this inhibition under normoxic conditions in mutant animals (Comt-/-) stabilises HIF-1 alpha by inactivating prolyl hydroxlases (PHD). We predict that a lack of inhibition of MnSOD, leading to persistent accumulation of HIF-1 alpha, would trigger inflammatory infiltration and endothelial damage in mutant animals. Critical tests of this hypothesis would be to recreate preeclampsia symptoms by inducing oxidative stress in WT animals or to ameliorate by treating mutant mice with Mn-SOD-catalase mimetics or activators of PHD

A low COMT activity haplotype is associated with recurrent preeclampsia in a Norwegian population cohort (HUNT2)

The etiology of preeclampsia is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. Although many candidate genes for preeclampsia have been suggested and studied, the specific causative genes still remain to be identified. Catechol-O-methyltransferase (COMT) is an enzyme involved in catecholamine and estrogen degradation and has recently been ascribed a role in development of preeclampsia. In the present study, we have examined the COMT gene by genotyping the functional Val108/158Met polymorphism (rs4680) and an additional single-nucleotide polymorphism, rs6269, predicting COMT activity haplotypes in a large Norwegian case/control cohort (ncases= 1135, ncontrols= 2262). A low COMT activity haplotype is associated with recurrent preeclampsia in our cohort. This may support the role of redox-regulated signaling and oxidative stress in preeclampsia pathogenesis as suggested by recent studies in a genetic mouse model. The COMT gene might be a genetic risk factor shared between preeclampsia and cardiovascular diseases

PADC nuclear track detector for ion spectroscopy in laser-plasma acceleration

[EN] The transparent polymer polyallyl-diglycol-carbonate (PADC), also known as CR-39, is widely used as detector for heavy charged particles at low fluence. It allows for detection of single protons and ions via formation of microscopic tracks after etching in NaOH or KOH solutions. PADC combines a high sensitivity and high specificity with inertness towards electromagnetic noise. Present fields of application include laser-ion acceleration, inertial confinement fusion, radiobiological studies with cell cultures, and dosimetry of nuclear fragments in particle therapy. These require precise knowledge of the energy-dependent response of PADC to different ion species. We present calibration data for a new type of detector material, Radosys RS39, to protons (0.2-3 MeV) and carbon ions (0.6-12 MeV). RS39 is less sensitive to protons than other types of PADC. Its response to carbon ions, however, is similar to other materials. Our data indicate that RS39 allows for measuring carbon ion energies up to 10 MeV only from the track diameters. In addition, it can be used for discrimination between protons and carbon ions in a single etching process.Project funded by CSIC, Grant No. 2018501082, and by the Spanish Ministerio de Ciencia, Innovacion y Universidades, project MdM-2016-0692-17-2 via a predoctoral grant of type Maria de Maeztu FPI. Nuclear track detector material and readout equipment have been provided by Radosys Ldt. (Budapest). The authors acknowledge the contributions and commitment of the CNA accelerator operators. MS would like to thank L. Ballesteros and J. Ortiz for their support with precision equipment.Seimetz, M.; Peñas, J.; Llerena, JJ.; Benlliure, J.; García López, J.; Millán-Callado, MA.; Benlloch Baviera, JM. (2020). PADC nuclear track detector for ion spectroscopy in laser-plasma acceleration. Physica Medica. 76:72-76. https://doi.org/10.1016/j.ejmp.2020.06.005S727676Kodaira, S., Kitamura, H., Kurano, M., Kawashima, H., & Benton, E. R. (2019). Contribution to dose in healthy tissue from secondary target fragments in therapeutic proton, He and C beams measured with CR-39 plastic nuclear track detectors. Scientific Reports, 9(1). doi:10.1038/s41598-019-39598-0Scampoli, P., Casale, M., Durante, M., Grossi, G., Pugliese, M., & Gialanella, G. (2001). Low-energy light ion irradiation beam-line for radiobiological studies. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 174(3), 337-343. doi:10.1016/s0168-583x(00)00622-4WADA, S., KOBAYASHI, Y., FUNAYAMA, T., NATSUHORI, M., ITO, N., & YAMAMOTO, K. (2002). Detection of DNA Damage in Individual Cells Induced by Heavy-ion Irradiation with an Non-denaturing Comet Assay. Journal of Radiation Research, 43(S), S153-S156. doi:10.1269/jrr.43.s153Gaillard, S., Pusset, D., de Toledo, S. M., Azzam, E. I., & Fromm, M. (2008). Distance distribution of bystander effects in alpha-particle irradiated cell populations using a CR-39-based culture dish. Radiation Measurements, 43, S34-S40. doi:10.1016/j.radmeas.2008.03.063Yogo, A., Maeda, T., Hori, T., Sakaki, H., Ogura, K., Nishiuchi, M., … Kondo, K. (2011). Measurement of relative biological effectiveness of protons in human cancer cells using a laser-driven quasimonoenergetic proton beamline. Applied Physics Letters, 98(5), 053701. doi:10.1063/1.3551623Séguin, F. H., Frenje, J. A., Li, C. K., Hicks, D. G., Kurebayashi, S., Rygg, J. R., … Padalino, S. (2003). Spectrometry of charged particles from inertial-confinement-fusion plasmas. Review of Scientific Instruments, 74(2), 975-995. doi:10.1063/1.1518141Daido, H., Nishiuchi, M., & Pirozhkov, A. S. (2012). Review of laser-driven ion sources and their applications. Reports on Progress in Physics, 75(5), 056401. doi:10.1088/0034-4885/75/5/056401Sinenian, N., Rosenberg, M. J., Manuel, M., McDuffee, S. C., Casey, D. T., Zylstra, A. B., … Petrasso, R. D. (2011). The response of CR-39 nuclear track detector to 1–9 MeV protons. Review of Scientific Instruments, 82(10), 103303. doi:10.1063/1.3653549Malinowska A, Szydłowski A, Jaskóła M, Korman A, Sartowska B, Kuehn T, Kuk M. Investigations of protons passing through the CR-39/PM-355 type of solid state nuclear track detectors, Rev Sci Instrum 84 (2013) 073511.Baccou, C., Yahia, V., Depierreux, S., Neuville, C., Goyon, C., Consoli, F., … Labaune, C. (2015). CR-39 track detector calibration for H, He, and C ions from 0.1-0.5 MeV up to 5 MeV for laser-induced nuclear fusion product identification. Review of Scientific Instruments, 86(8), 083307. doi:10.1063/1.4927684Seimetz, M., Bellido, P., García, P., Mur, P., Iborra, A., Soriano, A., … Benlloch, J. M. (2018). Spectral characterization of laser-accelerated protons with CR-39 nuclear track detector. Review of Scientific Instruments, 89(2), 023302. doi:10.1063/1.5009587Xiaojiao, D., Xiaofei, L., Zhixin, T., Yongsheng, H., Shilun, G., Dawei, Y., & Naiyan, W. (2009). Calibration of CR-39 with monoenergetic protons. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 609(2-3), 190-193. doi:10.1016/j.nima.2009.08.061Kodaira, S., Morishige, K., Kawashima, H., Kitamura, H., Kurano, M., Hasebe, N., … Ogura, K. (2016). A performance test of a new high-surface-quality and high-sensitivity CR-39 plastic nuclear track detector – TechnoTrak. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 383, 129-135. doi:10.1016/j.nimb.2016.07.002Ogura, K., Asano, M., Yasuda, N., & Yoshida, M. (2001). Properties of TNF-1 track etch detector. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 185(1-4), 222-227. doi:10.1016/s0168-583x(01)00816-3Malinowska, A., Jaskóła, M., Korman, A., Szydłowski, A., & Kuk, M. (2014). Characterization of solid state nuclear track detectors of the polyallyl-diglycol-carbonate (CR-39/PM-355) type for light charged particle spectroscopy. Review of Scientific Instruments, 85(12), 123505. doi:10.1063/1.4903755Bahrami, F., Mianji, F., Faghihi, R., Taheri, M., & Ansarinejad, A. (2016). Response of CR-39 to 0.9–2.5 MeV protons for KOH and NaOH etching solutions. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 813, 96-101. doi:10.1016/j.nima.2016.01.015Jeong, T. W., Singh, P. K., Scullion, C., Ahmed, H., Hadjisolomou, P., Jeon, C., … Ter-Avetisyan, S. (2017). CR-39 track detector for multi-MeV ion spectroscopy. Scientific Reports, 7(1). doi:10.1038/s41598-017-02331-wKanasaki, M., Hattori, A., Sakaki, H., Fukuda, Y., Yogo, A., Jinno, S., … Yamauchi, T. (2013). A high energy component of the intense laser-accelerated proton beams detected by stacked CR-39. Radiation Measurements, 50, 46-49. doi:10.1016/j.radmeas.2012.10.009Groza, A., Serbanescu, M., Butoi, B., Stancu, E., Straticiuc, M., Burducea, I., … Ganciu, M. (2019). Advances in Spectral Distribution Assessment of Laser Accelerated Protons using Multilayer CR-39 Detectors. Applied Sciences, 9(10), 2052. doi:10.3390/app9102052Zhang, Y., Wang, H.-W., Ma, Y.-G., Liu, L.-X., Cao, X.-G., Fan, G.-T., … Fang, D.-Q. (2019). Energy calibration of a CR-39 nuclear-track detector irradiated by charged particles. Nuclear Science and Techniques, 30(6). doi:10.1007/s41365-019-0619-xSeimetz, M., Bellido, P., Soriano, A., Garcia Lopez, J., Jimenez-Ramos, M. C., Fernandez, B., … Benlloch, J. M. (2015). Calibration and Performance Tests of Detectors for Laser-Accelerated Protons. IEEE Transactions on Nuclear Science, 62(6), 3216-3224. doi:10.1109/tns.2015.2480682Rana, M. A., & Qureshi, I. . (2002). Studies of CR-39 etch rates. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 198(3-4), 129-134. doi:10.1016/s0168-583x(02)01526-4Hermsdorf, D., Hunger, M., Starke, S., & Weickert, F. (2007). Measurement of bulk etch rates for poly-allyl-diglycol carbonate (PADC) and cellulose nitrate in a broad range of concentration and temperature of NaOH etching solution. Radiation Measurements, 42(1), 1-7. doi:10.1016/j.radmeas.2006.06.009Azooz, A. A., & Al-Jubbori, M. A. (2013). Interrelated temperature dependence of bulk etch rate and track length saturation time in CR-39 detector. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 316, 171-175. doi:10.1016/j.nimb.2013.09.001Jadrníčková I, Spurný F. To the spectrometry of linear energy transfer in charged particle beams by means of track-etch detectors, Radiat Measure 43(2008): S191–S194, proceedings of the 23rd International Conference on Nuclear Tracks in Solids. doi: 10.1016/j.radmeas.2008.04.010.Sadowski, M., Al-Mashhadani, E. M., Szydłowski, A., Czyzewski, T., Głowacka, L., Jaskóła, M., … Wieluński, M. (1995). Comparison of responses of CR-39 and PM-355 track detectors to fast protons, deuterons and 4He ions within energy range 0.2–4.5 MeV. Radiation Measurements, 25(1-4), 175-176. doi:10.1016/1350-4487(95)00066-nSadowski, M., Szydlowski, A., Jaskola, M., Czyzewski, T., & Kobzev, A. P. (1997). Comparison of responses of CR-39, PM-355, and CN track detectors to energetic hydrogen-, helium-, nitrogen-, and oxygen-ions. Radiation Measurements, 28(1-6), 207-210. doi:10.1016/s1350-4487(97)00069-3Henig, A., Steinke, S., Schnürer, M., Sokollik, T., Hörlein, R., Kiefer, D., … Habs, D. (2009). Radiation-Pressure Acceleration of Ion Beams Driven by Circularly Polarized Laser Pulses. Physical Review Letters, 103(24). doi:10.1103/physrevlett.103.245003Kar, S., Kakolee, K. F., Qiao, B., Macchi, A., Cerchez, M., Doria, D., … Borghesi, M. (2012). Ion Acceleration in Multispecies Targets Driven by Intense Laser Radiation Pressure. Physical Review Letters, 109(18). doi:10.1103/physrevlett.109.185006Palaniyappan, S., Huang, C., Gautier, D. C., Hamilton, C. E., Santiago, M. A., Kreuzer, C., … Fernández, J. C. (2015). Efficient quasi-monoenergetic ion beams from laser-driven relativistic plasmas. Nature Communications, 6(1). doi:10.1038/ncomms10170McGuffey, C., Raymond, A., Batson, T., Hua, R., Petrov, G. M., Kim, J., … Beg, F. N. (2016). Acceleration of high charge-state target ions in high-intensity laser interactions with sub-micron targets. New Journal of Physics, 18(11), 113032. doi:10.1088/1367-2630/18/11/113032Ma, W. J., Kim, I. J., Yu, J. Q., Choi, I. W., Singh, P. K., Lee, H. W., … Nam, C. H. (2019). Laser Acceleration of Highly Energetic Carbon Ions Using a Double-Layer Target Composed of Slightly Underdense Plasma and Ultrathin Foil. Physical Review Letters, 122(1). doi:10.1103/physrevlett.122.014803Hegelich, M., Karsch, S., Pretzler, G., Habs, D., Witte, K., Guenther, W., … Roth, M. (2002). MeV Ion Jets from Short-Pulse-Laser Interaction with Thin Foils. Physical Review Letters, 89(8). doi:10.1103/physrevlett.89.085002Henig, A., Kiefer, D., Markey, K., Gautier, D. C., Flippo, K. A., Letzring, S., … Hegelich, B. M. (2009). Enhanced Laser-Driven Ion Acceleration in the Relativistic Transparency Regime. Physical Review Letters, 103(4). doi:10.1103/physrevlett.103.045002Carroll, D. C., Tresca, O., Prasad, R., Romagnani, L., Foster, P. S., Gallegos, P., … McKenna, P. (2010). Carbon ion acceleration from thin foil targets irradiated by ultrahigh-contrast, ultraintense laser pulses. New Journal of Physics, 12(4), 045020. doi:10.1088/1367-2630/12/4/045020Jung, D., Yin, L., Albright, B. J., Gautier, D. C., Letzring, S., Dromey, B., … Hegelich, B. M. (2013). Efficient carbon ion beam generation from laser-driven volume acceleration. New Journal of Physics, 15(2), 023007. doi:10.1088/1367-2630/15/2/023007Dollar, F., Zulick, C., Matsuoka, T., McGuffey, C., Bulanov, S. S., Chvykov, V., … Krushelnick, K. (2013). High contrast ion acceleration at intensities exceeding 1021 Wcm−2. Physics of Plasmas, 20(5), 056703. doi:10.1063/1.4803082Kohno, R., Yasuda, N., Takeshi, H., Kase, Y., Ochiai, K., Komori, M., … Kanai, T. (2005). Measurements of Dose-Averaged Linear Energy Transfer Distributions in Water Using CR-39 Plastic Nuclear Track Detector for Therapeutic Carbon Ion Beams. Japanese Journal of Applied Physics, 44(12), 8722-8726. doi:10.1143/jjap.44.8722Romo, V., Rickards, J., Espinosa, G., & Golzarri, J. I. (1999). The Response of CR-39 Polycarbonate to Energetic Carbon Ions. Radiation Protection Dosimetry, 85(1), 459-461. doi:10.1093/oxfordjournals.rpd.a032897Szydlowski, A., Czyzewski, T., Jaskola, M., Sadowski, M., Korman, A., Kedzierski, J., & Kretschmer, W. (1999). Investigation of response of CR-39, PM-355 and PM-500 types of nuclear track detectors to energetic carbon ions. Radiation Measurements, 31(1-6), 257-260. doi:10.1016/s1350-4487(99)00125-

Elevation of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline: a blood pressure-independent beneficial effect of angiotensin I-converting enzyme inhibitors

Blockade of the renin-angiotensin system (RAS) is well recognized as an essential therapy in hypertensive, heart, and kidney diseases. There are several classes of drugs that block the RAS; these drugs are known to exhibit antifibrotic action. An analysis of the molecular mechanisms of action for these drugs can reveal potential differences in their antifibrotic roles. In this review, we discuss the antifibrotic action of RAS blockade with an emphasis on the potential importance of angiotensin I-converting enzyme (ACE) inhibition associated with the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP)

Proliferative and anti-proliferative effects of dietary levels of phytoestrogens in rat pituitary GH3/B6/F10 cells - the involvement of rapidly activated kinases and caspases

<p>Abstract</p> <p>Background</p> <p>Phytoestogens are a group of lipophillic plant compounds that can have estrogenic effects in animals; both tumorigenic and anti-tumorigenic effects have been reported. Prolactin-secreting adenomas are the most prevalent form of pituitary tumors in humans and have been linked to estrogen exposures. We examined the proliferative effects of phytoestrogens on a rat pituitary tumor cell line, GH₃/B₆/F₁₀, originally subcloned from GH₃cells based on its ability to express high levels of the membrane estrogen receptor-α.</p> <p>Methods</p> <p>We measured the proliferative effects of these phytoestrogens using crystal violet staining, the activation of several mitogen-activated protein kinases (MAPKs) and their downstream targets via a quantitative plate immunoassay, and caspase enzymatic activities.</p> <p>Results</p> <p>Four phytoestrogens (coumestrol, daidzein, genistein, and <it>trans</it>-resveratrol) were studied over wide concentration ranges. Except <it>trans</it>-resveratrol, all phytoestrogens increased GH₃/B₆/F₁₀cell proliferation at some concentration relevant to dietary levels. All four phytoestrogens attenuated the proliferative effects of estradiol when administered simultaneously. All phytoestrogens elicited MAPK and downstream target activations, but with time course patterns that often differed from that of estradiol and each other. Using selective antagonists, we determined that MAPKs play a role in the ability of these phytoestrogens to elicit these responses. In addition, except for <it>trans</it>-resveratrol, a serum removal-induced extrinsic apoptotic pathway was blocked by these phytoestrogens.</p> <p>Conclusion</p> <p>Phytoestrogens can block physiological estrogen-induced tumor cell growth <it>in vitro </it>and can also stimulate growth at high dietary concentrations in the absence of endogenous estrogens; these actions are correlated with slightly different signaling response patterns. Consumption of these compounds should be considered in strategies to control endocrine tumor cell growth, such as in the pituitary.</p