Are serum Netrin-4 levels predictive of preeclampsia?
, 1, 1, 1, 2, 3, 1, 1
Abstract
Objective: To investigate the levels of anti-angiogenic factors, namely sFlt-1 and Netrin-4, in patients with preeclampsia (PE). Material and methods: Cord-blood (UC) sFlt-1 and Netrin-4 concentrations were measured in 30 patients with severe PE, 30 patients with PE and 30 control infants and their mothers (MS). Results: Maternal sFlt-1 levels were significantly higher in the severe PE and PE groups than in the control group. There were no statistical differences among the three groups in maternal and fetal Netrin-4 levels. But Netrin-4 levels were found to be the lowest in the control group and higher in the PE and severe PE groups. The correlation analysis revealed a positive correlation between maternal sFlt-1 levels and maternal Netrin-4 levels (p = 0.012, and r = 0.263), maternal sFlt-1 levels and fetal sFlt-1 levels (p = 0.012, and r = 0.263). Conclusions: There was a positive correlation found between maternal sFlt-1 levels and maternal Netrin-4 levels. We are of the opinion that elevation in levels of Netrin-4 might be secondary to placental hypoxia occurring in PE. The present study led to the consideration of anti-angiogenic biomarkers (sFlt-1 and Netrin-4) on automated platforms for clinical use as an aid in establishing the diagnosis and prognosis of PE.
Keywords: sFlt-1Netrin-4preeclampsiaanti-angiogenic effects
References
- American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013; 122(5): 1122–1131.
- Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003; 111(5): 649–658.
- Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. The Lancet. 2005; 365(9461): 785–799.
- Maynard SE, Karumanchi SA. Angiogenic factors and preeclampsia. Semin Nephrol. 2011; 31(1): 33–46.
- Kwiatkowski S, Kwiatkowska E, Torbe A. The role of disordered angiogenesis tissue markers (sflt-1, Plgf) in present day diagnosis of preeclampsia. Ginekol Pol. 2019; 90(3): 173–176.
- Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997; 18(1): 4–25.
- Shibuya M. VEGF-VEGFR Signals in Health and Disease. Biomol Ther (Seoul). 2014; 22(1): 1–9.
- Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004; 350(7): 672–683.
- Boutsikou T, Giotaki M, Gourgiotis D, et al. Cord blood netrin-1 and -4 concentrations in term pregnancies with normal, restricted and increased fetal growth. J Matern Fetal Neonatal Med. 2014; 27(18): 1849–1853.
- Dakouane-Giudicelli M, Alfaidy N, de Mazancourt P. Netrins and their roles in placental angiogenesis. Biomed Res Int. 2014; 2014: 901941.
- Koch M, Murrell JR, Hunter DD, et al. A novel member of the netrin family, beta-netrin, shares homology with the beta chain of laminin: identification, expression, and functional characterization. J Cell Biol. 2000; 151(2): 221–234.
- Kociok N, Crespo-Garcia S, Liang Y, et al. Lack of netrin-4 modulates pathologic neovascularization in the eye. Sci Rep. 2016; 6: 18828.
- Eveno C, Broqueres-You D, Feron JG, et al. Netrin-4 delays colorectal cancer carcinomatosis by inhibiting tumor angiogenesis. Am J Pathol. 2011; 178(4): 1861–1869.
- Han Y, Shao Yi, Liu T, et al. Therapeutic effects of topical netrin-4 inhibits corneal neovascularization in alkali-burn rats. PLoS One. 2015; 10(4): e0122951.
- Polliotti B. Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia. Obstetrics & Gynecology. 2003; 101(6): 1266–1274.
- Staff AC, Braekke K, Harsem NK, et al. Circulating concentrations of sFlt1 (soluble fms-like tyrosine kinase 1) in fetal and maternal serum during pre-eclampsia. Eur J Obstet Gynecol Reprod Biol. 2005; 122(1): 33–39.
- Cim N, Kurdoglu M, Ege S, et al. An analysis on the roles of angiogenesis-related factors including serum vitamin D, soluble endoglin (sEng), soluble fms-like tyrosine kinase 1 (sFlt1), and vascular endothelial growth factor (VEGF) in the diagnosis and severity of late-onset preeclampsia. J Matern Fetal Neonatal Med. 2017; 30(13): 1602–1607.
- Liu Y, Zhao Y, Yu A, et al. Diagnostic accuracy of the soluble Fms-like tyrosine kinase-1/placental growth factor ratio for preeclampsia: a meta-analysis based on 20 studies. Arch Gynecol Obstet. 2015; 292(3): 507–518.
- Lange J, Yafai Y, Noack A, et al. The axon guidance molecule Netrin-4 is expressed by Müller cells and contributes to angiogenesis in the retina. Glia. 2012; 60(10): 1567–1578.
- Dakouane-Giudicelli M, Brouillet S, Traboulsi W, et al. Inhibition of human placental endothelial cell proliferation and angiogenesis by netrin-4. Placenta. 2015; 36(11): 1260–1265.
- Cao B, Meng X, Fu Y, et al. Neuron-derived netrin-1 and netrin-4 proteins are additional effective targets in diabetic retinopathy beyond VEGF. Int J Clin Exp Pathol. 2017;10(8):8174-86. PubMed PMID: 31966669; PubMed Central PMCID. : PMC6965419.
- Nacht M, St Martin TB, Byrne A, et al. Netrin-4 regulates angiogenic responses and tumor cell growth. Exp Cell Res. 2009; 315(5): 784–794.
