Evidence of proteinuria, but no other characteristics of pre-eclampsia, in relaxin-deficient mice
Kelly P. O’Sullivan A , Sarah A. Marshall A , Scott Cullen A , Tahnee Saunders A , Natalie J. Hannan B , Sevvandi N. Senadheera A and Laura J. Parry A C
+ Author Affiliations
- Author Affiliations
A School of BioSciences, The University of Melbourne, Parkville, Vic., 3010, Australia.
B The Translational Obstetrics Group, Mercy Hospital for Women, Department of Obstetrics and Gynaecology, The University of Melbourne, Vic., 3010, Australia.
C Corresponding author. Email: ljparry@unimelb.edu.au
Reproduction, Fertility and Development 29(8) 1477-1485 https://doi.org/10.1071/RD16056
Submitted: 2 February 2016 Accepted: 7 June 2016 Published: 4 August 2016
Abstract
Pre-eclampsia (PE) is a leading cause of maternal and fetal death, characterised by an imbalance of placental growth factors and hypertension at >20 weeks gestation. Impaired maternal systemic vascular adaptations and fetal growth restriction are features of both PE and pregnant relaxin-deficient (Rln–/–) mice. The aim of the present study was to investigate whether these phenotypes in Rln–/– mice are associated with abnormal placental growth factor expression, increased soluble fms-like tyrosine kinase-1 (sFlt-1), proteinuria and/or hypertension during pregnancy. In addition, we examined relaxin and relaxin receptor (relaxin/insulin like family peptide receptor 1 (RXFP1)) mRNA expression in placentas of women with PE. There was no significant difference in placental vascular endothelial growth factor A (VegfA) and placenta growth factor (Plgf) gene expression between Rln–/– and wild-type mice. Circulating plasma sFlt-1 concentrations in pregnant mice of both genotypes and ages were increased compared with non-pregnant mice but were lower in younger pregnant Rln–/– mice compared with aged-matched Rln+/+ mice. Aged pregnant Rln–/– mice had higher urinary albumin : creatinine ratios compared with age-matched Rln+/+ mice, indicative of proteinuria. Systolic and diastolic blood pressures did not differ between genotypes. In addition, PE in women was not associated with altered placental mRNA expression of RLN2 or RXFP1 at term. Overall, the data demonstrate that pregnant Rln–/– mice do not have the typical characteristics of PE. However, these mice show evidence of proteinuria, but we suggest that this results from systemic renal vascular dysfunction before pregnancy.
Additional keywords: placental growth factor, relaxin/insulin like family peptide receptor 1 (RXFP1), vascular endothelial growth factor.
References
Adamson, S. L., Lu, Y., Whiteley, K. J., Holmyard, D., Hemberger, M., Pfarrer, C., and Cross, J. C. (2002). Interactions between trophoblast cells and the maternal and fetal circulation in the mouse placenta. Dev. Biol. 250, 358–373.| Interactions between trophoblast cells and the maternal and fetal circulation in the mouse placenta.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XnsFSnt74%3D&md5=01fbffbcc2c571f89e39612bf217ed76CAS | 12376109PubMed |
Anumba, D. O., El Gelany, S., Elliott, S. L., and Li, T. C. (2009). Serum relaxin levels are reduced in pregnant women with a history of recurrent miscarriage, and correlate with maternal uterine artery Doppler indices in first trimester. Eur. J. Obstet. Gynecol. Reprod. Biol. 147, 41–45.
| Serum relaxin levels are reduced in pregnant women with a history of recurrent miscarriage, and correlate with maternal uterine artery Doppler indices in first trimester.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXht1OnsL3P&md5=8834e2ed64391908735df79b645ccbb7CAS | 19695764PubMed |
Bond, C. P., Parry, L. J., Samuel, C. S., Gehring, H. M., Lederman, F. L., Rogers, P. A., and Summers, R. J. (2004). Increased expression of the relaxin receptor (LGR7) in human endometrium during the secretory phase of the menstrual cycle. J. Clin. Endocrinol. Metab. 89, 3477–3485.
| Increased expression of the relaxin receptor (LGR7) in human endometrium during the secretory phase of the menstrual cycle.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXlslegt7s%3D&md5=1fcafb4c3dcf96063b11667f7c8e9b67CAS | 15240635PubMed |
Bridges, J. P., Gilbert, J. S., Colson, D., Gilbert, S. A., Dukes, M. P., Ryan, M. J., and Granger, J. P. (2009). Oxidative stress contributes to soluble fms-like tyrosine kinase-1 induced vascular dysfunction in pregnant rats. Am. J. Hypertens. 22, 564–568.
| Oxidative stress contributes to soluble fms-like tyrosine kinase-1 induced vascular dysfunction in pregnant rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXkvVGqs70%3D&md5=48682058c66d965c315c5435522a4bfbCAS | 19265787PubMed |
Clements, M. E., Chaber, C. J., Ledbetter, S. R., and Zuk, A. (2013). Increased cellular senescence and vascular rarefaction exacerbate the progression of kidney fibrosis in aged mice following transient ischemic injury. PLoS One 8, e70464.
| Increased cellular senescence and vascular rarefaction exacerbate the progression of kidney fibrosis in aged mice following transient ischemic injury.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhtlSmsbnK&md5=c6eee8907a5c79728092cb7db5fe4dfdCAS | 23940580PubMed |
Conrad, K. P. (2011a). Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia. Semin. Nephrol. 31, 15–32.
| Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhtVWqtLo%3D&md5=11a2bf493298b138661fab05e550b6a2CAS | 21266262PubMed |
Conrad, K. P. (2011b). Maternal vasodilation in pregnancy: the emerging role of relaxin. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R267–R275.
| Maternal vasodilation in pregnancy: the emerging role of relaxin.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhtFSrtb%2FK&md5=39ebe7324a775b7630f578936cadbe83CAS | 21613576PubMed |
Danielson, L. A., Sherwood, O. D., and Conrad, K. P. (1999). Relaxin is a potent renal vasodilator in conscious rats. J. Clin. Invest. 103, 525–533.
| Relaxin is a potent renal vasodilator in conscious rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXhslWqsLs%3D&md5=2a8f70a3e2a25944aa256d386636106eCAS | 10021461PubMed |
Danielson, L. A., Kercher, L. J., and Conrad, K. P. (2000). Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R1298–R1304.
| 1:CAS:528:DC%2BD3cXns1egt7g%3D&md5=104489d1357c1cd35e1a6c3b8bf9cae6CAS | 11003996PubMed |
Debrah, D. O., Novak, J., Matthews, J. E., Ramirez, R. J., Shroff, S. G., and Conrad, K. P. (2006). Relaxin is essential for systemic vasodilation and increased global arterial compliance during early pregnancy in conscious rats. Endocrinology 147, 5126–5131.
| Relaxin is essential for systemic vasodilation and increased global arterial compliance during early pregnancy in conscious rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XhtFCgsL3N&md5=451948fe9baf03b381b281874cfffeffCAS | 16873529PubMed |
Debrah, D. O., Debrah, J. E., Haney, J. L., McGuane, J. T., Sacks, M. S., Conrad, K. P., and Shroff, S. G. (2011). Relaxin regulates vascular wall remodeling and passive mechanical properties in mice. J. Appl. Physiol. 111, 260–271.
| Relaxin regulates vascular wall remodeling and passive mechanical properties in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXpvF2jsL4%3D&md5=d8e9814d47c77a461e5f610695d1f77bCAS | 21551018PubMed |
George, E. M., and Granger, J. P. (2011). VEGF: a possible therapeutic for the treatment of preeclampsia? Expert Rev. Obstet. Gynecol. 6, 255–257.
| VEGF: a possible therapeutic for the treatment of preeclampsia?Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXmslalsL4%3D&md5=20d511ea2ef15456cef1078dd34a0775CAS |
Ghulmiyyah, L., and Sibai, B. (2012). Maternal mortality from preeclampsia/eclampsia. Semin. Perinatol. 36, 56–59.
| Maternal mortality from preeclampsia/eclampsia.Crossref | GoogleScholarGoogle Scholar | 22280867PubMed |
Gooi, J. H., Richardson, M. L., Jelinic, M., Girling, J. E., Wlodek, M. E., Tare, M., and Parry, L. J. (2013). Enhanced uterine artery stiffness in aged pregnant relaxin mutant mice is reversed with exogenous relaxin treatment. Biol. Reprod. 89, 18.
| Enhanced uterine artery stiffness in aged pregnant relaxin mutant mice is reversed with exogenous relaxin treatment.Crossref | GoogleScholarGoogle Scholar | 23718984PubMed |
Goulopoulou, S., and Davidge, S. T. (2015). Molecular mechanisms of maternal vascular dysfunction in preeclampsia. Trends Mol. Med. 21, 88–97.
| Molecular mechanisms of maternal vascular dysfunction in preeclampsia.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2MXitF2jsrk%3D&md5=8118ffcc2de4084c13144a236f6c18a8CAS | 25541377PubMed |
Hewitt, D. P., Mark, P. J., and Waddell, B. P. (2006). Glucocorticoids prevent the normal increase in placental vascular endothelial growth factor expression and placental vascularity during late pregnancy in the rat. Endocrinology 147, 5568–5574.
| Glucocorticoids prevent the normal increase in placental vascular endothelial growth factor expression and placental vascularity during late pregnancy in the rat.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28Xht1yqtr7M&md5=b907d1a3ff0fdb1c2bf40da0fdae3db8CAS | 16959835PubMed |
Jeyabalan, A., Stewart, D. R., McGonigal, S. C., Powers, R. W., and Conrad, K. P. (2009). Low relaxin concentrations in the first trimester are associated with increased risk of developing preeclampsia. Reprod. Sci. 16, 101A..
Kanasaki, K., Palmsten, K., Sugimoto, H., Ahmad, S., Hamano, Y., Xie, L., Parry, S., Augustin, H. G., Gattone, V. H. G., Folkman, J., Strauss, J. F., and Kalluri, R. (2008). Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature 453, 1117–1121.
| Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXntlGjtLc%3D&md5=72956e89aa7c3773412bd127121c9b6bCAS | 18469803PubMed |
Knobil, E., and Neill, J. D. (1994). Natural history and mechanisms of reproductive aging in humans, laboratory rodents, and other selected vertebrates. In ‘The Physiology of Reproduction’. (Eds E. Knobil and J. D. Neill.) pp. 1213–1314. (Raven Press: New York.)
Leo, C. H., Jelinic, M., Gooi, J. H., Tare, M., and Parry, L. J. (2014). A vasoactive role for endogenous relaxin in mesenteric arteries of male mice. PLoS One 9, e107382.
| A vasoactive role for endogenous relaxin in mesenteric arteries of male mice.Crossref | GoogleScholarGoogle Scholar | 25243460PubMed |
Levine, R. J., Maynard, S. E., Qian, C., Lim, K. H., England, L. J., Yu, K. F., Schisterman, E. F., Thadhani, R., Sachs, B. P., Epstein, F. H., Sibai, B. M., Sukhatme, V. P., and Karumanchi, S. A. (2004). Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 350, 672–683.
| Circulating angiogenic factors and the risk of preeclampsia.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXhtFCrt7w%3D&md5=bae7898bdf784a799756a544138da78aCAS | 14764923PubMed |
Lowndes, K., Amano, A., Yamamoto, S. Y., and Bryant-Greenwood, G. D. (2006). The human relaxin receptor (LGR7): expression in the fetal membranes and placenta. Placenta 27, 610–618.
| The human relaxin receptor (LGR7): expression in the fetal membranes and placenta.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XjvVagtrg%3D&md5=255a5164e12292427679121abe9cc8a5CAS | 16165207PubMed |
Lu, F., Longo, M., Tamayo, E., Maner, W., Al-Hendy, A., Anderson, G. D., Hankins, G. D., and Saade, G. R. (2007). The effect of over-expression of sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in unrestrained conscious pregnant mice. Am. J. Obstet. Gynecol. 196, 396.e1–396.e7.
| The effect of over-expression of sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in unrestrained conscious pregnant mice.Crossref | GoogleScholarGoogle Scholar |
Ma, J. -F., Von Kalle, M., Plautz, Q., Xu, F. -M., Singh, L., and Wang, L. (2013). Relaxin promotes in vitro tumour growth, invasion and angiogenesis of human Saos-2 osteosarcoma cells by AKT/VEGF pathway. Eur. Rev. Med. Pharmacol. Sci. 17, 1345–1350.
| 23740448PubMed |
Marshall, S. A., Leo, C. H., Senadheera, S. N., Girling, J. E., Tare, M., and Parry, L. J. (2016). Relaxin deficiency attenuates pregnancy-induced adaptation of the mesenteric artery to angiotensin II in mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310, R847–R857.
| Relaxin deficiency attenuates pregnancy-induced adaptation of the mesenteric artery to angiotensin II in mice.Crossref | GoogleScholarGoogle Scholar | 26936785PubMed |
Matsumoto, K., and Ema, M. (2014). Roles of VEGF-A signalling in development, regeneration, and tumours. J. Biochem. 156, 1–10.
| Roles of VEGF-A signalling in development, regeneration, and tumours.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhtFShsrfE&md5=2922989ebab7bb87d665ca3d5f38d51aCAS | 24839295PubMed |
Maynard, S. E., Min, J. -Y., Merchan, J., Lim, K. H., Li, J., Mondal, S., Libermann, T. A., Morgan, J. P., Sellke, F. W., Stillman, I. E., Epstein, F. H., Sukhatme, V. P., and Karumanchi, S. A. (2003). Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 111, 649–658.
| Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXhvFentbc%3D&md5=eddd7f8c3636359b1950f4060b23381aCAS | 12618519PubMed |
Millar, L. K., Reiny, R., Yamamoto, S. Y., Okazaki, K., Webster, L., and Bryant-Greenwood, G. D. (2003). Relaxin causes proliferation of human amniotic epithelium by stimulation of insulin-like growth factor-II. Am. J. Obstet. Gynecol. 188, 234–241.
| Relaxin causes proliferation of human amniotic epithelium by stimulation of insulin-like growth factor-II.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXhsV2nsL0%3D&md5=aa76f9119e420136139a8ff4140f0141CAS | 12548223PubMed |
Mirabito, K. M., Hilliard, L. M., Wei, Z., Tikellis, C., Widdop, R. E., Vinh, A., and Denton, K. M. (2014). Role of inflammation and the angiotensin type 2 receptor in the regulation of arterial pressure during pregnancy in mice. Hypertension 64, 626–631.
| Role of inflammation and the angiotensin type 2 receptor in the regulation of arterial pressure during pregnancy in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhsV2lsbfJ&md5=8d7f7ab2945eafc853b0c63806b2eb34CAS | 24935937PubMed |
Novak, J., Danielson, L. A., Kerchner, L. J., Sherwood, O. D., Ramirez, R. J., Moalli, P. A., and Conrad, K. P. (2001). Relaxin is essential for renal vasodilation during pregnancy in conscious rats. J. Clin. Invest. 107, 1469–1475.
| Relaxin is essential for renal vasodilation during pregnancy in conscious rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXktFyntLw%3D&md5=d592d2d955eeed4b2f322fd972d1e6b0CAS | 11390429PubMed |
Novak, J., Ramirez, R. J., Gandley, R. E., Sherwood, O. D., and Conrad, K. P. (2002). Myogenic reactivity is reduced in small renal arteries isolated from relaxin-treated rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283, R349–R355.
| 1:CAS:528:DC%2BD38XmslShsbs%3D&md5=12935200518329d4ae65fc809ff77268CAS | 12121847PubMed |
Novak, J., Parry, L. J., Matthews, J. E., Kerchner, L. J., Indoniva, K., Hanley-Yanez, K., Doty, K. D., Debrah, D. O., Shroff, S. G., and Conrad, K. P. (2006). Evidence for local relaxin ligand–receptor expression and function in arteries. FASEB J. 20, 2352–2362.
| Evidence for local relaxin ligand–receptor expression and function in arteries.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XhtFylsrbK&md5=fe63f4a060645928113fa6c7481479a8CAS | 17077312PubMed |
Ogueh, O., Clough, A., Hancock, M., and Johnson, M. R. (2011). A longitudinal study of the control of renal and uterine hemodynamic changes of pregnancy. Hypertens. Pregnancy 30, 243–259.
| A longitudinal study of the control of renal and uterine hemodynamic changes of pregnancy.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXoslOhtr4%3D&md5=344829444d22e18832ad21e67a60fcd3CAS | 21740248PubMed |
Palejwala, S., Tseng, L., Wojtczuk, A., Weiss, G., and Goldsmith, L. T. (2002). Relaxin gene and protein expression and its regulation of procollagenase and vascular endothelial growth factor in human endometrial cells. Biol. Reprod. 66, 1743–1748.
| Relaxin gene and protein expression and its regulation of procollagenase and vascular endothelial growth factor in human endometrial cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XjvFegurc%3D&md5=7aeb1e888fbe83b4a27c4681032b3f50CAS | 12021056PubMed |
Palmer, K. R., Kaitu’u-Lino, T. J., Hastie, R., Hannan, N. J., Ye, L., Binder, N., Cannon, P., Tuohey, L., Johns, T. G., Shub, A., and Tong, S. (2015). Placental-specific sFLT-1 e15a protein is increased in preeclampsia, antagonizes vascular endothelial growth factor signaling, and has antiangiogenic activity. Hypertension 66, 1251–1259.
| 1:CAS:528:DC%2BC2MXhvFCls7jF&md5=a0ad8a9ad85ea20a396b4aa3619f1be9CAS | 26416849PubMed |
Parry, L. J., and Vodstrcil, L. A. (2007). Relaxin physiology in the female reproductive tract during pregnancy. Adv. Exp. Med. Biol. 612, 34–48.
| Relaxin physiology in the female reproductive tract during pregnancy.Crossref | GoogleScholarGoogle Scholar | 18161480PubMed |
Pijnenborg, R., Vercruysse, L., and Hanssens, M. (2006). The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 27, 939–958.
| The uterine spiral arteries in human pregnancy: facts and controversies.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD28vptlSjuw%3D%3D&md5=07dd8efa80e3da51f5a91c4ee6f1de96CAS | 16490251PubMed |
Poppas, A., Shroff, S. G., Korcarz, C. E., Hibbard, J. U., Berger, D. S., Lindheimer, M. D., and Lang, R. M. (1997). Serial assessment of the cardiovascular system in normal pregnancy: role of arterial compliance and pulsatile arterial load. Circulation 95, 2407–2415.
| Serial assessment of the cardiovascular system in normal pregnancy: role of arterial compliance and pulsatile arterial load.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK2szhsVSlsA%3D%3D&md5=e0f4ab0ba8bf41bd13efe1393c88413eCAS | 9170404PubMed |
Powe, C. E., Levine, R. J., and Karumanchi, S. A. (2011). Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. Circulation 123, 2856–2869.
| Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease.Crossref | GoogleScholarGoogle Scholar | 21690502PubMed |
Schaarschmidt, W., Rana, S., and Stepan, H. (2013). The course of angiogenic factors in early- vs. late-onset preeclampsia and HELLP syndrome. J. Perinat. Med. 41, 511–516.
| The course of angiogenic factors in early- vs. late-onset preeclampsia and HELLP syndrome.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXms1Chtb0%3D&md5=84a30719501bc98acca5ba0e8ffa704fCAS | 23612628PubMed |
Smith, M. C., Murdoch, A. P., Danielson, L. A., Conrad, K. P., and Davison, J. M. (2006). Relaxin has a role in establishing a renal response in pregnancy. Fertil. Steril. 86, 253–255.
| Relaxin has a role in establishing a renal response in pregnancy.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XotV2jtrw%3D&md5=0afca7cff4f5ac86cc0e43ae12df1b0bCAS | 16730722PubMed |
Stewart, D. R., Celniker, A. C., Taylor, C. A., Cragun, J. R., Overstreet, J. W., and Lasley, B. L. (1990). Relaxin in the peri-implantation period. J. Clin. Endocrinol. Metab. 70, 1771–1773.
| Relaxin in the peri-implantation period.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK3c3ntVeqtg%3D%3D&md5=f0e6e2c8edf05ea250cbdaa0b243ae37CAS | 2347909PubMed |
Tranquilli, A. L., Dekker, G., Magee, L., Roberts, J., Sibai, B. M., Steyn, W., Zeeman, G. G., and Brown, M. A. (2014). The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP. Pregnancy Hypertens. 4, 97–104.
| The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BC2Mbms1WhsQ%3D%3D&md5=f5a981b8c6d42942c8cb5efbd9179c42CAS | 26104417PubMed |
Uiterweer, E. D. P., Koster, M. P., Jeyabalan, A., Kuc, S., Siljee, J., Conrad, K. P., and Franx, A. (2014). First trimester serum relaxin concentration and prediction of early and late onset preeclampsia. Reprod. Sci. 21, 394A.
Unemori, E. N., Erikson, M. E., Rocco, S. E., Sutherland, K. M., Parsell, D. A., Mak, J., and Grove, B. H. (1999). Relaxin stimulates expression of vascular endothelial growth factor in normal human endometrial cells in vitro and is associated with menometrorrhagia in women. Hum. Reprod. 14, 800–806.
| Relaxin stimulates expression of vascular endothelial growth factor in normal human endometrial cells in vitro and is associated with menometrorrhagia in women.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXisV2qtrw%3D&md5=dd85a414bb2a43062f7a93f51b4a2e91CAS | 10221717PubMed |
Vodstrcil, L. A., Shynlova, O., Westcott, K., Laker, R., Simpson, E., Wlodek, M. E., and Parry, L. J. (2010). Progesterone withdrawal, and not increased circulating relaxin, mediates the decrease in myometrial relaxin receptor (RXFP1) expression in late gestation in rats. Biol. Reprod. 83, 825–832.
| Progesterone withdrawal, and not increased circulating relaxin, mediates the decrease in myometrial relaxin receptor (RXFP1) expression in late gestation in rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtlGls7%2FP&md5=d5c6f429d8e31b21b3c6a2ade2dab5eaCAS | 20686183PubMed |
Vodstrcil, L. A., Tare, M., Novak, J., Dragomir, N., Ramirez, R. J., Wlodek, M. E., Conrad, K. P., and Parry, L. J. (2012). Relaxin mediates uterine artery compliance during pregnancy and increases uterine blood flow. FASEB J. 26, 4035–4044.
| Relaxin mediates uterine artery compliance during pregnancy and increases uterine blood flow.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhsFSmtbrE&md5=c1cc5d2619f80295b5985267872022b2CAS | 22744867PubMed |
Vrachnis, N., Kalampokas, E., Sifakis, S., Vitoratos, N., Kalampokas, T., Botsis, D., and Iliodromiti, Z. (2013). Placental growth factor (PlGF): a key to optimizing fetal growth. J. Matern. Fetal Neonatal Med. 26, 995–1002.
| Placental growth factor (PlGF): a key to optimizing fetal growth.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXptFCgtrc%3D&md5=af1451abcb1a1a705e9bac369f620e0fCAS | 23330778PubMed |
Walter, L. M., Rogers, P. A. W., and Girling, J. E. (2005). The role of progesterone in endometrial angiogenesis in pregnant and ovariectomised mice. Reproduction 129, 765–777.
| The role of progesterone in endometrial angiogenesis in pregnant and ovariectomised mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXlvFGit70%3D&md5=626f39741f8cf976574d00d0aed2a94dCAS | 15923392PubMed |
Woods, A. K., Hoffman, D. S., Weydert, C. J., Butler, S. D., Zhou, R. V., and Davisson, R. L. (2011). Adenoviral delivery of VEGF121 early in pregnancy prevents spontaneous development of preeclampsia in BPH/5 mice. Hypertension 57, 94–102.
| Adenoviral delivery of VEGF121 early in pregnancy prevents spontaneous development of preeclampsia in BPH/5 mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhsFGku7zO&md5=c5e754dfd0407c60976def2df850084cCAS | 21079047PubMed |
Zhao, L., Roche, P., Gunnersen, J. M., Hammond, V. E., Tregear, G. W., Wintour, E. M., and Beck, F. (1999). Mice without a functional relaxin gene are unable to deliver milk to their pups. Endocrinology 140, 445–453.
| 1:CAS:528:DyaK1MXhtFWrtg%3D%3D&md5=45ccde8e2bac76c96e432839ba80f526CAS | 9886856PubMed |
