Soluble FLT-1 in angiogenesis: pathophysiological roles and therapeutic implications

Fine-tuning angiogenesis, the development of new blood vessels, is essential for maintaining a healthy circulatory and lymphatic system. The small glycoprotein vascular endothelial growth factors (VEGF) are the key mediators in this process, binding to their corresponding membrane-bound VEGF receptors (VEGFRs) to activate angiogenesis signaling pathways. These pathways are crucial throughout human life as they are involved in lymphatic and vascular endothelial cell permeability, migration, proliferation, and survival. Neovascularization, the formation of abnormal blood vessels, occurs when there is a dysregulation of angiogenesis and can result in debilitating disease. Hence, VEGFRs have been widely studied to understand their role in disease-causing angiogenesis. VEGFR1, also known as Fms-like tyrosine kinase-1 (FLT-1), is also found in a soluble form, soluble FLT-1 or sFLT-1, which is known to act as a VEGF neutralizer. It is incorporated into anti-VEGF therapy, designed to treat diseases caused by neovascularization. Here we review the journey of sFLT-1 discovery and delve into the alternative splicing mechanism that creates the soluble receptor, its prevalence in disease states, and its use in current and future potential therapies.