FLT1 (VEGFR-1): A Bidirectional Regulator of Angiogenesis and an Emerging Therapeutic Target

1. Background of FLT1

1.1 Biological Characteristics and Functions

FLT1 (VEGFR-1) is a member of the vascular endothelial growth factor receptor (VEGFR) family and belongs to the typical Type III receptor tyrosine kinases. Its structure comprises seven extracellular immunoglobulin-like domains, a single transmembrane region, and an intracellular tyrosine kinase domain ^[1]. Alternatively spliced soluble FLT1 (sFLT1) lacks the transmembrane and kinase domains but retains VEGF-binding capacity, functioning as an endogenous VEGF signaling antagonist ^[2]. Crystallographic studies reveal that FLT1 and VEGF-A form a 1:2 complex, where the second immunoglobulin-like domain (D2) determines ligand recognition, while D3 participates in receptor dimerization and activation ^[3]. FLT1 exhibits differential affinity for VEGF family ligands, binding VEGF-B and Placental Growth Factor (PlGF) with higher affinity than VEGFR-2.

During angiogenesis, FLT1 exerts regulatory functions through dual mechanisms: membrane-bound FLT1, upon activation, recruits Gab1, subsequently activating the PI3K-Akt-mTOR pathway to promote endothelial cell migration ^[4]; whereas sFLT1 maintains vascular homeostasis by neutralizing free VEGF and inhibiting excessive angiogenesis ^[1]. Studies show that FLT1 knockout mice are embryonically lethal due to abnormal vascular development, a phenotype distinct from VEGFR-2 deficiency ^[2]. Phosphorylation of tyrosine 1210 in the FLT1 kinase domain specifically activates the HIF-1α-VEGF positive feedback loop, amplifying pro-angiogenic signals under hypoxic conditions ^[4]. Furthermore, FLT1 regulates Rho GTPase activity via non-canonical pathways, influencing endothelial cytoskeletal reorganization and lumen formation ^[3].

FLT1 function relies on dynamic glycosylation modifications. N-linked glycosylation affects receptor membrane localization and controls signaling intensity by modulating ligand-binding affinity. Under pathological conditions, metalloproteinase ADAM17-mediated shedding of the FLT1 extracellular domain generates sFLT1 fragments, a process significantly induced by TNF-α and oxidative stress ^[1]. FLT1 exhibits angiogenesis-independent functions in specific tissues, such as activating the TrkB pathway to regulate synaptic plasticity in neurons and inhibiting MMP-13 expression to delay matrix degradation in chondrocytes ^[3][4]. This multifunctionality positions FLT1 as a critical node connecting the vascular system and the microenvironment.

1.2 Positioning within the VEGF Family

The vascular endothelial growth factor (VEGF) family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, and Placental Growth Factor (PlGF), with their receptors being FLT1 (VEGFR-1), KDR (VEGFR-2), and FLT4 (VEGFR-3) ^[5]. FLT1 was the first identified VEGF receptor, showing higher binding specificity for VEGF-B and PlGF compared to VEGFR-2, but possesses weaker kinase activity, primarily serving regulatory functions ^[1].

FLT1 and VEGFR-2 complementarily regulate angiogenesis: VEGFR-2 mediates endothelial proliferation, migration, and increased permeability, whereas FLT1 maintains vascular homeostasis by competitively binding VEGF-A to inhibit excessive VEGFR-2 activation, or by activating the PLCγ-PKC-MAPK pathway ^[5]. FLT1 knockout mice die due to excessive vascular hyperplasia, while transgenic mice expressing only the extracellular truncated form of FLT1 survive normally, indicating that its negative regulatory role primarily relies on a ligand trapping mechanism ^[3]. The PlGF-FLT1 axis can activate the PI3K/Akt pathway under pathological conditions, promoting vascular remodeling and playing a key role in ischemic diseases and tumor angiogenesis ^[6].

FLT1 cooperates with VEGFR-3 to regulate blood-lymphatic vessel balance. VEGFR-3 responds to VEGF-C/D to promote lymphangiogenesis, while FLT1 enhances the sensitivity of lymphatic endothelial cells to low concentrations of VEGF-C through the formation of heterodimers ^[1]. In wound repair models, FLT1 deficiency can lead to approximately a 40% reduction in lymphatic vessel density ^[3]. sFLT1 acts as a natural antagonist by binding circulating VEGF-A and PlGF to regulate vascular permeability, and its abnormally elevated levels are associated with the pathogenesis of pre-eclampsia ^[5]. Proteomic studies show that sFLT1 affinity for VEGF-A165 is 5-fold higher than that of VEGFR-2, but its inhibitory effect on VEGF-A121 is limited; this isoform selectivity offers targeted strategies for treating vascular diseases ^[2].

1.3 FLT1 Expression Regulatory Mechanisms

FLT1 expression is regulated at multiple levels:

• Hypoxia: HIF-1α binds to the hypoxia response element in the FLT1 promoter, upregulating transcription ^[7].
• Oxidative Stress: ROS activates NF-κB, stabilizing FLT1 mRNA and increasing protein levels 2-3 fold ^[8].
• Epigenetics: 5-azacytidine reduces promoter CpG island methylation, increasing expression by 40% in bone marrow stromal cells.
• miRNA Regulation: miR-206 inhibits FLT1 translation, while miR-210 is downregulated under hypoxia, indirectly enhancing expression ^[3].
• Inflammatory Cytokines: TNF-α induces peak expression within 6 hours via p38 MAPK/NF-κB/AP-1 ^[7].
• Mechanical Stress: Fluid shear stress triggers calcium signaling via Piezo1, creating spatial heterogeneity in FLT1 expression in arterial endothelium, with expression reduced by approximately 35% in high-shear stress regions ^[8].
• Hormonal Regulation: The glucocorticoid receptor binds the promoter to inhibit transcription, and Notch signaling effector Hes1 competitively binds enhancer regions to suppress expression ^[3][4].

2. Research Mechanisms of FLT1

2.1 Canonical Signaling Pathways

FLT1 binding to VEGF induces dimerization, autophosphorylation, and recruitment of adaptor proteins like Akt, forming a signaling complex ^[4].

• Akt Pathway: Inhibits GSK-3β and activates mTORC1, promoting endothelial survival and migration, while concurrently upregulating HIF-1α stability ^[8]
• HIF-1α Positive Feedback: Enhances VEGF transcription under hypoxia, amplifying angiogenic signals ^[9]
• PLCγ-PKC-MAPK: Regulates vascular homeostasis and migration

VEGF stimulation exhibits spatiotemporal specificity, enhancing vascular permeability in the short term and promoting angiogenesis in the long term ^[5]. FLT1 forms heterodimers with VEGFR-2 to coordinately regulate PI3K-Akt and ERK1/2 branches; Akt phosphorylation levels positively correlate with microvessel density. TNF-α can inhibit HIF-1α via NF-κB, blocking the FLT1-VEGF positive feedback loop and leading to impaired angiogenesis ^[8].

2.2 Synergistic Effects with Other Receptors

FLT1 forms complexes with VEGFR-2, with FLT1 biased towards the PLCγ-PKC-MAPK pathway and VEGFR-2 towards the PI3K-Akt pathway ^[4]. Under hypoxia, FLT1 competitively binds VEGF-B/PlGF, reducing excessive VEGFR-2 activation and maintaining vascular homeostasis ^[5]. The receptor ratio and phosphorylation status dynamically balance signal output, while changes in sFLT1 levels further fine-tune angiogenesis ^[2][5]. In cartilage repair, changes in the FLT1/VEGFR-2 ratio affect vascular invasion and MMP-9 secretion, providing a favorable microenvironment for tissue engineering ^[5].

2.3 Signaling Network Regulatory Patterns

• Positive Feedback: HIF-1α/FLT1 enhances VEGF expression ^[9]
• Negative Feedback: sFLT1 neutralizes VEGF, PTP1B mediates dephosphorylation, c-Cbl mediates degradation ^[10][11]
• Homeostatic Imbalance: Over-activation leads to tumor vascular hyperplasia, while over-inhibition hinders tissue repair ^[4]

Network pharmacology studies indicate that natural products and compound formulations can achieve vascular homeostasis by modulating FLT1 and its downstream signals ^[11].