Soluble fms-like tyrosine kinase-1 (sFlt-1 or sVEGFR-1) is a

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

protein with

antiangiogenic An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical d ...

properties. A non-membrane associated

splice variant Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...

of VEGF receptor 1 (Flt-1), sFlt-1 binds the angiogenic factors

VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

(vascular endothelial growth factor) and

PlGF Placental growth factor (PlGF) is a protein that in humans is encoded by the ''PGF'' gene. Placental growth factor is a member of the VEGF (vascular endothelial growth factor) sub-family - a key molecule in angiogenesis and vasculogenesis, in p ...

(placental growth factor), reducing blood vessel growth through reduction of free

and

concentrations. In humans, sFlt-1 is important in the regulation of blood vessel formation in diverse tissues, including the

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...

, and

uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...

. Abnormally high levels of sFlt-1 have been implicated in the pathogenesis of

preeclampsia Pre-eclampsia is a multi-system disorder specific to pregnancy, characterized by the new onset of high blood pressure and often a significant amount of protein in the urine or by the new onset of high blood pressure along with significant end- ...

Structure

sFlt-1 is a truncated form of the VEGF receptor Flt-1. Though sFlt-1 contains an extracellular domain identical to that of Flt-1, it lacks both the transmembrane and intercellular domains present in Flt-1. Instead, sFlt-1 contains a novel 31 amino acid C-terminal sequence. sFlt-1 is composed of 6 immunoglobulin-like domains, with a binding site for VEGF and PIGF within the second domain from the N-terminus. A sequence of 10 basic amino acids form a binding site for the anticoagulant

heparin Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Heparin is a blood anticoagulant that increases the activity of antithrombin. It is used in the treatment of myocardial infarction, ...

in the third domain from the N-terminus. sFlt-1 has a pI of 9.51, giving the protein a positive charge at

physiological pH Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a subdiscipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out chemical and ...

Biological function

Because sFlt-1 lacks the

transmembrane domain A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...

that typically embeds tyrosine kinase receptors in the cell membrane, sFlt-1 travels freely in the blood circulation, and thus can travel from the tissue in which it is originally secreted to other areas of the body. As it contains the same

extracellular domain An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction. A notabl ...

as Flt-1, sFlt-1 competes with Flt-1 to bind VEGF and PIGF, effectively reducing serum concentrations of these two angiogenic growth factors. Though sFlt-1 can effectively dimerize, its lack of a kinase domain means that no

tyrosine phosphorylation Tyrosine phosphorylation is the addition of a phosphate () group to the amino acid tyrosine on a protein. It is one of the main types of protein phosphorylation. This transfer is made possible through enzymes called tyrosine kinases. Tyrosine phos ...

occurs upon ligand binding. As a result, sFlt-1 effectively sequesters agonists of Flt-1, and has been implicated as a regulator of this receptor in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

, and

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

Role in preeclampsia

The placental factor theory of preeclampsia

Preeclampsia is a pregnancy-specific condition characterized by maternal hypertension and

proteinuria Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become fo ...

after the 20th week of

gestation Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregn ...

. Normally, during early formation of the

placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

, extravillous cytotrophoblasts, a type of specialized fetal cell, enter the

spiral arteries Spiral arteries are small arteries which temporarily supply blood to the endometrium of the uterus during the luteal phase of the menstrual cycle. In histology, identifying the presence of these arteries is one of the most useful techniques in id ...

of the

. This invasion spurs remodeling of the epithelial layer of these uterine arteries, increasing their conductance and decreasing their resistance to meet the increase blood flow demands of pregnancy. Specifically, invading cytotrophoblasts achieve this change by down-regulating the expression of

adhesion molecules Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...

characteristic of

epithelial cells Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

and up-regulating the expression of adhesion molecules characteristic of

endothelial cells The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

in a process known as pseudovasculogenesis. In preeclamptic patients, this arterial transformation is incomplete, as cytotrophoblasts fail to completely switch their adhesion molecule expression pattern to an endothelial form. The balance of pro- and anti-angiogenic factors and their receptors, including

VEGF-A Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the ''VEGFA'' gene. Function This gene is a member of the platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF) family and encod ...

, PIGF, Flt1, and sFlt1, is thought to mediate this process. In women who develop preeclampsia, the sFlt-1 to PlGF ratio is higher than in normal pregnancy. sFlt-1 produced in the placenta is thought to circulate in the maternal bloodstream to act on distant tissues, explaining the multi-system

endothelial dysfunction In blood vessel diseases, endothelial dysfunction is an unhealthy state of the the cells that line the blood vessels (endothelium). The main cause of endothelial dysfunction is impaired bioavailability of nitric oxide. In addition to acting a ...

observed in women with preeclampsia. In-vitro studies have linked sFlt-1 treatment to a pattern of

vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vesse ...

and endothelial dysfunction identical to the syndrome produced when cells are incubated with serum from preeclamptic patients. Additionally,

adenoviral Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from the ...

transfer of the sFlt-1 gene to pregnant rats has been shown to produce a syndrome similar to preeclampsia.

Preeclamptic regulation of sFlt-1

Though sFlt-1 is produced in small amounts by

and

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

s, the placenta is theorized to be the major source of sFlt-1 during pregnancy. sFlt-1

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

shows strong expression in the placenta, and serum concentration of sFlt-1 falls significantly in patients after delivery of the placenta. Expression of sFlt-1 is stimulated by

hypoxic Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of a specific environment ** Hypoxia in fish, responses of fish to hypoxia * Hypoxia (medi ...

conditions. In healthy pregnancies, the placenta develops in a hypoxic environment, leading to a 20-fold increase in sFlt-1 expression. In early-onset preeclamptic patients, this increase is estimated to be up to 43 times more pronounced, and may be spurred by conditions of poor uterine profusion leading to more severe local hypoxia. Inhibition of nitric oxide signaling has also been associated with elevation of serum sFlt-1 in a rat model of preeclampsia; this stimulus may represent a secondary factor contributing to sFlt-1 trends in human preeclampsia as well. In addition to short-term regulation by oxygen and nitric oxide levels, genetic differences also influence Flt-1 gene splicing and resulting sFlt-1 expression levels. Women with histories of preeclampsia continue to show elevated serum levels of sFlt-1 up to 18 months

postpartum The postpartum (or postnatal) period begins after childbirth and is typically considered to last for six to eight weeks. There are three distinct phases of the postnatal period; the acute phase, lasting for six to twelve hours after birth; the ...

, suggesting a genetic basis of sFlt-1 expression independent of pregnancy-related stimuli.

Clinical significance

PlGF and sFlt-1 concentrations measured by

immunoassay An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoassay ...

in maternal blood improve the prognostic possibilities in preeclampsia, which is typically diagnosed solely on the basis of clinical symptoms, proteinuria, and uterine artery Doppler velocimetry. Notably, increases in sFlt-1 and decreases in PIGF and VEGF can be detected at least five weeks before the onset of preeclamptic symptoms, potentially facilitating earlier diagnosis and treatment. sFlt-1 changes are most predictive of early-onset preeclampsia; cases of preeclampsia incident late in pregnancy typically are accompanied only by small decreases in PIGF. However, sFlt-1 elevation is also associated with other obstetric conditions such as non-preeclampsic interuterine growth retardation of the fetus, limiting its use as a discriminatory

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

for preeclampsia. Additionally,

sensitivity and specificity In medicine and statistics, sensitivity and specificity mathematically describe the accuracy of a test that reports the presence or absence of a medical condition. If individuals who have the condition are considered "positive" and those who do ...

of sFlt-1 testing is generally considered too low to enable it to serve as an effective predictor of preeclampsia. sFlt-1 involvement in the pathogenesis of preeclampsia may explain several demographic trends in incidence of the condition. The human Flt-1/sFlt-1 gene is located at 13q12; the association of fetal trisomy-13 with higher rates of preeclampsia could theoretically be explained by the additional copy of the gene. Additionally,

primiparous In biology and medicine, gravidity and parity are the number of times a female has been pregnant (gravidity) and carried the pregnancies to a viable gestational age (parity). These two terms are usually coupled, sometimes with additional terms, t ...

women have higher baseline levels of sFlt-1, a trend which could potentially explain the higher incidence of preeclampsia among first-time mothers.

Citations

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