Journal of Reproductive Immunology 100 (2013) 128
Contents lists available at ScienceDirect
Journal of Reproductive Immunology journal homepage: www.elsevier.com/locate/jreprimm
Letter to the Editor The role of the VEGF-C signaling pathway in preeclampsia? We read with interest the review paper by Rakova et al. (2013) about novel findings in sodium metabolism, volume regulation, and the (possible) links with pregnancy and preeclampsia. The authors review the involvement of the immune system in pregnancy and preeclampsia, with a specific link to the novel paradigm of sodium homeostasis. Recent studies showed that sodium can be stored non-osmotically in a newly discovered subcutaneous interstitial compartment via macrophages acting as osmosensors. These macrophages activate the vascular endothelial growth factor (VEGF)-C signaling pathway, which subsequently modifies the lymph–capillary network in the skin and enhances production of vasodilatory nitric oxide in the skin vessels via the VEGF receptors VEGFR3 and VEGFR-2, respectively. Indeed, human studies have shown that in healthy men and in proteinuric chronic kidney disease (CKD) patients, VEGF-C is modulated by salt intake, with higher VEGF-C levels during high salt intake. At either high or low sodium intake VEGF-C levels were higher in the proteinuric patients, i.e., the population with salt-sensitive blood pressure and edema, with disturbed overall sodium balance, and altered volume distribution over body compartments (Slagman et al., 2011). Rakova et al. (2013) link old literature on sodium homeostasis during pregnancy and preeclampsia, and hypothesize that the new sodium paradigm might be relevant to the pathogenesis of preeclampsia. Although little is known about the new sodium concept in preeclamptic women, we would like to point out that there are data available, albeit limited, on VEGF-C and its signaling pathway in preeclampsia. Groten et al. (2010) have shown that VEGFR-2 expression was significantly reduced in the syncytiotrophoblast and endothelium of the placenta of preeclamptic women. Moreover, a recent study showed reduced soluble VEGFR2 in preeclampsia in both plasma and placental tissue (Munaut et al., 2012). With respect to the balance of VEGF-C and its receptors, at a gestational age of 34 weeks, preeclamptic women have a lower soluble VEGFR3 + VEGFR-2/VEGF-C ratio than normal pregnant women (Lely et al., 2013), suggesting that preeclampsia may be characterized by an enhanced lymphangiogenic state, in an interesting parallel with the observation in proteinuric CKD patients. These alterations could be secondary to sodium retention in these patients, and/or be involved 0165-0378/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jri.2013.10.002
in the altered regulation of interstitial sodium and fluid turnover, and blood pressure. The response of VEGF-C to altered sodium intake in preeclamptic women, however, is still unknown. The “new sodium paradigm” on VEGF-C and its signaling pathway and its possible role in the pathogenesis of preeclampsia is an area of opportunities. In the above studies preeclamptic women show a relatively pro-lymphangiogenic state, parallel to proteinuric CKD patients. Future studies should explore the pathophysiological and clinical relevance of the novel concept of sodium, VEGF-C, and its downstream effects on interstitial sodium regulation in preeclampsia. To this end, studies investigating the responses to altered sodium intake in (formerly) preeclamptic women would be the logical first step. References Groten, T., et al., 2010. Differential expression of VE-cadherin and VEGFR2 in placental syncytiotrophoblast during preeclampsia – new perspectives to explain the pathophysiology. Placenta 31 (4), 339–343. Lely, A.T., et al., 2013. Circulating lymphangiogenic factors in preeclampsia. Hypertens. Pregnancy 32 (1), 42–49. Munaut, C., et al., 2012. Differential expression of Vegfr-2 and its soluble form in preeclampsia. PLoS One 7 (3), e33475. Rakova, N., et al., 2013. Novel ideas about salt, blood pressure, and pregnancy. J. Reprod. Immunol., http://dx.doi.org/10.1016/ j.jri.2013.04.001. Slagman, M.C., et al., 2011. Vascular endothelial growth factor C levels are modulated by dietary salt intake in proteinuric chronic kidney disease patients and in healthy subjects. Nephrol. Dial. Transplant. 27 (3), 978–982.
Tsjitske J. Toering ∗ Gerjan Navis Department of Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands A. Titia Lely Department of Obstetrics & Gynaecology, University of Groningen, University Medical Center Groningen, The Netherlands ∗ Corresponding
author. Tel.: +31 503616161. E-mail address: [email protected] (T.J. Toering) 10 July 2013
Contents lists available at ScienceDirect
Journal of Reproductive Immunology journal homepage: www.elsevier.com/locate/jreprimm
Letter to the Editor The role of the VEGF-C signaling pathway in preeclampsia? We read with interest the review paper by Rakova et al. (2013) about novel findings in sodium metabolism, volume regulation, and the (possible) links with pregnancy and preeclampsia. The authors review the involvement of the immune system in pregnancy and preeclampsia, with a specific link to the novel paradigm of sodium homeostasis. Recent studies showed that sodium can be stored non-osmotically in a newly discovered subcutaneous interstitial compartment via macrophages acting as osmosensors. These macrophages activate the vascular endothelial growth factor (VEGF)-C signaling pathway, which subsequently modifies the lymph–capillary network in the skin and enhances production of vasodilatory nitric oxide in the skin vessels via the VEGF receptors VEGFR3 and VEGFR-2, respectively. Indeed, human studies have shown that in healthy men and in proteinuric chronic kidney disease (CKD) patients, VEGF-C is modulated by salt intake, with higher VEGF-C levels during high salt intake. At either high or low sodium intake VEGF-C levels were higher in the proteinuric patients, i.e., the population with salt-sensitive blood pressure and edema, with disturbed overall sodium balance, and altered volume distribution over body compartments (Slagman et al., 2011). Rakova et al. (2013) link old literature on sodium homeostasis during pregnancy and preeclampsia, and hypothesize that the new sodium paradigm might be relevant to the pathogenesis of preeclampsia. Although little is known about the new sodium concept in preeclamptic women, we would like to point out that there are data available, albeit limited, on VEGF-C and its signaling pathway in preeclampsia. Groten et al. (2010) have shown that VEGFR-2 expression was significantly reduced in the syncytiotrophoblast and endothelium of the placenta of preeclamptic women. Moreover, a recent study showed reduced soluble VEGFR2 in preeclampsia in both plasma and placental tissue (Munaut et al., 2012). With respect to the balance of VEGF-C and its receptors, at a gestational age of 34 weeks, preeclamptic women have a lower soluble VEGFR3 + VEGFR-2/VEGF-C ratio than normal pregnant women (Lely et al., 2013), suggesting that preeclampsia may be characterized by an enhanced lymphangiogenic state, in an interesting parallel with the observation in proteinuric CKD patients. These alterations could be secondary to sodium retention in these patients, and/or be involved 0165-0378/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jri.2013.10.002
in the altered regulation of interstitial sodium and fluid turnover, and blood pressure. The response of VEGF-C to altered sodium intake in preeclamptic women, however, is still unknown. The “new sodium paradigm” on VEGF-C and its signaling pathway and its possible role in the pathogenesis of preeclampsia is an area of opportunities. In the above studies preeclamptic women show a relatively pro-lymphangiogenic state, parallel to proteinuric CKD patients. Future studies should explore the pathophysiological and clinical relevance of the novel concept of sodium, VEGF-C, and its downstream effects on interstitial sodium regulation in preeclampsia. To this end, studies investigating the responses to altered sodium intake in (formerly) preeclamptic women would be the logical first step. References Groten, T., et al., 2010. Differential expression of VE-cadherin and VEGFR2 in placental syncytiotrophoblast during preeclampsia – new perspectives to explain the pathophysiology. Placenta 31 (4), 339–343. Lely, A.T., et al., 2013. Circulating lymphangiogenic factors in preeclampsia. Hypertens. Pregnancy 32 (1), 42–49. Munaut, C., et al., 2012. Differential expression of Vegfr-2 and its soluble form in preeclampsia. PLoS One 7 (3), e33475. Rakova, N., et al., 2013. Novel ideas about salt, blood pressure, and pregnancy. J. Reprod. Immunol., http://dx.doi.org/10.1016/ j.jri.2013.04.001. Slagman, M.C., et al., 2011. Vascular endothelial growth factor C levels are modulated by dietary salt intake in proteinuric chronic kidney disease patients and in healthy subjects. Nephrol. Dial. Transplant. 27 (3), 978–982.
Tsjitske J. Toering ∗ Gerjan Navis Department of Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands A. Titia Lely Department of Obstetrics & Gynaecology, University of Groningen, University Medical Center Groningen, The Netherlands ∗ Corresponding
author. Tel.: +31 503616161. E-mail address: [email protected] (T.J. Toering) 10 July 2013
