Fms-like tyrosine kinase 1 (FLT1) is a protein receptor found on the surface of various cells, particularly those lining blood vessels. It is a member of the vascular endothelial growth factor (VEGF) receptor family, formally designated as VEGFR-1. FLT1 plays a role in angiogenesis, the formation of new blood vessels from pre-existing ones. By binding to growth factors like VEGF and Placental Growth Factor (PlGF), FLT1 helps orchestrate the development and maintenance of the body’s circulatory network.
The Basic Biological Role of FLT1
The full-length FLT1 protein is a membrane-bound receptor tyrosine kinase anchored to endothelial cells. Its primary function is to bind Vascular Endothelial Growth Factor-A (VEGF-A) with very high affinity, approximately ten times greater than its companion receptor, VEGFR-2. This high-affinity binding causes FLT1 to act largely as a “ligand sink” or negative regulator, limiting free VEGF available to activate the main signaling receptor, VEGFR-2. This sequestration mechanism controls blood vessel growth during normal development.
Although FLT1 is often described as having weak signaling compared to VEGFR-2, it does initiate specific cellular pathways. FLT1 is a key regulator of endothelial cell migration within the fetoplacental unit. It also plays a role in attracting macrophage-lineage cells (monocyte chemotaxis) to sites of inflammation or tissue repair. Thus, FLT1’s normal physiological role involves actively guiding cell movement and passively modulating the overall strength of the pro-angiogenic signal.
The Soluble Form: sFLT1
FLT1 also exists as a truncated version called soluble FLT1 (sFLT1). This molecule is produced through alternative splicing of the FLT1 gene, resulting in a protein that contains the extracellular portion of the receptor but lacks the transmembrane and intracellular signaling domains. Because it is not anchored to a cell membrane, sFLT1 is released into the bloodstream and circulates freely.
The main function of sFLT1 is to act as a decoy or trap for circulating angiogenic factors. Once released, sFLT1 binds to Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF). By capturing these growth factors, sFLT1 prevents them from reaching and activating their full-length receptors on the surface of endothelial cells. This action makes sFLT1 a potent anti-angiogenic molecule, reducing pro-growth signaling in the maternal circulation.
FLT1’s Central Role in Preeclampsia
The biological mechanism of sFLT1 is central to the pathology of preeclampsia, a serious complication of pregnancy characterized by new-onset hypertension and proteinuria after 20 weeks of gestation. In preeclamptic pregnancies, the placenta releases excessive amounts of sFLT1 into the maternal circulation. This overproduction is triggered by conditions like placental hypoxia, which results from poor remodeling of the maternal spiral arteries early in pregnancy.
The surge of sFLT1 shifts the balance of angiogenic factors in the bloodstream. High levels of sFLT1 sequester nearly all available free VEGF and PlGF, leaving the mother’s blood vessels starved of necessary growth factors. This profound angiogenic imbalance leads to widespread endothelial dysfunction, where the cells lining the blood vessels function incorrectly.
This endothelial damage affects various maternal organs, causing the characteristic symptoms of preeclampsia. In the kidneys, damage to the endothelial lining of the filtration units (glomeruli) leads to the leakage of protein into the urine (proteinuria). Dysfunction in the small vessels throughout the body results in vasoconstriction, causing the elevation in blood pressure (hypertension). This pathology can also affect the liver and brain, leading to severe complications like seizures (eclampsia) and organ failure.
Clinical Applications and Testing
The discovery of the sFLT1 imbalance has led to clinical applications in the management of pregnancy. Clinicians utilize a blood test that measures the ratio of soluble FLT1 to Placental Growth Factor (sFLT1/PlGF) in pregnant patients suspected of developing preeclampsia. This ratio provides a direct, quantifiable measure of the angiogenic balance in the maternal circulation.
A high sFLT1/PlGF ratio indicates that the anti-angiogenic factor (sFLT1) is dominant, suggesting a high risk for the onset or progression of preeclampsia. Conversely, a low ratio (often defined by a specific cutoff value) has a very high negative predictive value. This means that a low ratio can reliably rule out the development of preeclampsia in the short term, often for the following one to four weeks.
The results of this ratio test guide management decisions, helping to triage patients and allocate resources. A result indicating low risk may allow a physician to safely manage a patient with suspected preeclampsia on an outpatient basis, avoiding unnecessary hospitalization. Conversely, a high-risk ratio prompts closer maternal and fetal monitoring and informs the decision about the optimal timing for delivery, which is the only definitive treatment for preeclampsia.
FLT1 in Other Conditions
While FLT1 is most recognized for its role in preeclampsia, its signaling pathways are involved in a variety of other diseases featuring abnormal blood vessel growth. In cancer, FLT1 signaling can promote tumor growth and metastasis by recruiting specific immune cells that support the tumor environment. The formation of new blood vessels (tumor angiogenesis) is necessary to supply rapidly dividing cancer cells with oxygen and nutrients.
This understanding has positioned the VEGF/FLT1 system as a target for anti-angiogenic cancer therapies. Drugs that block the activity of VEGF or its receptors are used to “starve” tumors by cutting off their blood supply. FLT1 is also implicated in several ocular diseases, including wet age-related macular degeneration and diabetic retinopathy, which are characterized by pathological growth of new blood vessels in the retina. Therapies for these eye conditions often involve local injections of drugs designed to inhibit VEGF signaling.