- Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1, also known as Flt-1) is one of the three main receptors in the VEGF receptor family.
- It plays a complex and somewhat paradoxical role in vascular biology, as it can both promote and inhibit angiogenesis depending on the context.
- VEGFR-1 is a receptor tyrosine kinase expressed on endothelial cells, monocytes, macrophages, and some other cell types. Its primary ligands are VEGF-A, VEGF-B, and placental growth factor (PlGF).
- VEGFR-1 has a very high binding affinity for VEGF-A—higher than VEGFR-2—but its intrinsic tyrosine kinase activity is relatively weak. Because of this, one of its major functions is to act as a “decoy receptor” by sequestering VEGF-A, thereby preventing excessive activation of VEGFR-2, which is the main driver of angiogenesis. This regulatory role is particularly important during embryonic vascular development, where VEGFR-1 helps fine-tune the balance between vessel growth and maturation. In fact, mice lacking VEGFR-1 die in utero due to uncontrolled endothelial proliferation, underscoring its critical role in modulating angiogenesis.
- In addition to its decoy function, VEGFR-1 also has active signaling roles. Through its activation by VEGF-B and PlGF, it can promote endothelial cell migration, mobilization of bone marrow–derived progenitor cells, and recruitment of monocytes and macrophages to sites of inflammation or tumor growth. This makes VEGFR-1 a key player in linking angiogenesis with inflammatory and immune processes. In pathological conditions such as cancer, PlGF/VEGFR-1 signaling contributes to tumor angiogenesis, metastasis, and the recruitment of immune cells that support tumor progression. Similarly, in diseases such as rheumatoid arthritis or ischemic heart disease, VEGFR-1 pathways can influence inflammatory vascular responses.
- Another important form of VEGFR-1 is soluble VEGFR-1 (sFlt-1), a truncated version of the receptor that lacks the transmembrane and intracellular domains. It is secreted into the circulation, where it binds VEGF and PlGF, reducing their availability for signaling. sFlt-1 plays an important role in pregnancy: it is produced by the placenta to help regulate vascular growth in the uterine environment. However, excessive sFlt-1 production is strongly implicated in preeclampsia, a hypertensive disorder of pregnancy, by sequestering VEGF and PlGF, leading to endothelial dysfunction and maternal hypertension.
