Soluble fms-like tyrosine kinase-1

Soluble fms-like tyrosine kinase-1 (sFlt-1 or sVEGFR-1) is a tyrosine kinase protein that disables proteins that cause blood vessel growth. Soluble Flt-1 (sFlt-1) is a splice variant of VEGF receptor 1 (Flt-1) which is produced by a variety of tissues.^[1]These proteins act as a receptor of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor. (Another VEGF receptor is KDR).

sFlt-1 (soluble fms-like tyrosine kinase-1 – also known as soluble VEGF receptor-1) binds and reduces free circulating levels of the proangiogenic factors VEGF (vascular endothelial growth factor) and PlGF (placental growth factor). sFlt-1 thereby blunts the beneficial effects of these proangiogenic factors on maternal endothelium, with consequent maternal hypertension and proteinuria. Serum levels of PlGF and sFlt-1 are altered in women with preeclampsia. Moreover, circulating levels of PlGF and sFlt-1 can discriminate between a normal pregnancy and that with preeclampsia even prior to clinical presentation, and sFlt-1 and PlGF are associated with disease severity and the onset of symptoms.^[2]

In normal pregnancy, the pro-angiogenic factor PlGF increases during the first two trimesters and decreases as pregnancy progresses to term. In contrast, levels of the anti-angiogenic factor sFlt-1 remain stable during the early and middle stages of gestation and increase steadily until term. In women who develop preeclampsia, sFlt-1 levels have been found to be higher and PlGF levels have been found to be lower than in normal pregnancy.^{[3][4] [5][6]}

In uncomplicated pregnancies, blood pressure changes from mid-to-late pregnancy, in particular for diastolic blood pressure and mean arterial pressure, are inversely correlated with maternal PlGF concentrations at delivery and positively correlated with the ratio of sFlt1/PlGF. In preeclamptic pregnancies, the mean second-trimester blood pressure measurement is inversely correlated with PlGF and positively correlated with the sFlt1/PlGF ratio.²

Maternal sFlt1 has been shown to be significantly higher in incidences of severe preeclampsia, as compared with mild forms of the disease, as well as with uncomplicated pregnancies. Both balance in circulating angiogenic factor and blood pressure modulation in pregnancy may be a continuum, with the diagnosis of preeclampsia at the extreme. Most studies indicate that preeclamptic features are not unique to preeclampsia, existing in normal pregnancies as well, albeit at a lower level.²

The ratio of sFlt-1 to PlGF has been shown to be a better predictor of preeclampsia than either measure alone.^[7]

In summary, PlGF and sFlt-1 concentrations measured by immunoassay in maternal blood improve the diagnostic possibilities in preeclampsia which comprise clinical symptoms, proteinuria, and uterine artery Doppler velocimetry.^[8][9]

References

1. Khalil A, Muttukrishna S, Harrington K, Jauniaux E, 2008 Effect of Antihypertensive Therapy with Alpha Methyldopa on Levels of Angiogenic Factors in Pregnancies with Hypertensive Disorders. PLoS ONE 3(7): e2766. doi:10.1371/journal.pone.0002766
2. Troisi, Rebecca, Kristin Braekke, Nina Kittelsen Harsem, Marianne Hyer, Robert N. Hoover, and Anne C. Staff. "Blood pressure augmentation and maternal circulating concentrations of angiogenic factors at delivery in preeclamptic and uncomplicated pregnancies." Am J Obstet Gynecol 199(6): 653.e1-653.10.1016/j.ajog.2008.06.030.
3. Maynard SE, 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;111:649-658.
4. Levine RJ, et al. Urinary Placental Growth Factor and Risk of Preeclampsia. JAMA 2005;293:77-85.
5. Kendall R, Thomas K. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 1993;90:10705-10709.
6. Lam C, Lim KH, Karumanchi S. Circulating Angiogenic Factors in the Pathogenesis and Prediction of Preeclampsia. Hypertension Res 2005;46:1077-1085.
7. Bushimschi C, et al. Urinary angiogenic factors cluster hypertensive disorders and identify women with severe preeclampsia. Am J Obstet Gynecol 2005;192:734-741.
8. Thadhani R, et al. First Trimester Placental Growth Factor and Soluble Fms-Like Tyrosine Kinase 1 and Risk for Preeclampsia. J Clin Endo 2004;89(2):770-775.
9. Hirashima C, et al. Establishing Reference Values for Both Total Soluble Fms-Like Tyrosine Kinase 1 and Free Placental Growth Factor in Pregnant Woman. Hypertens Res 2005;28:727-732.