- Placental growth factor-2 (PlGF-2) is a splice variant of placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family that regulates angiogenesis, vasculogenesis, and tissue remodeling in both physiological and pathological contexts.
- PlGF-2 is generated by alternative splicing of the PGF gene and differs structurally from PlGF-1 by the presence of an additional basic heparin-binding domain at the carboxy-terminal end. This structural feature allows PlGF-2 to bind not only to VEGF receptor-1 (VEGFR-1/Flt-1) but also to heparan sulfate proteoglycans and neuropilins, enhancing its ability to interact with the extracellular matrix and cell surface co-receptors. As a result, PlGF-2 tends to localize more tightly to tissues and extracellular matrices than PlGF-1, which is freely diffusible.
- Functionally, PlGF-2 shares many angiogenic and immunomodulatory roles with PlGF-1, but its additional receptor interactions give it broader and more potent biological effects. Through VEGFR-1 activation, PlGF-2 stimulates endothelial cell proliferation, migration, and survival, while also recruiting monocytes, macrophages, and bone marrow–derived progenitor cells to sites of injury or ischemia. By binding neuropilin-1 and neuropilin-2, PlGF-2 can further modulate VEGF-A signaling through VEGFR-2, amplifying angiogenesis and vascular permeability. Its capacity to attach to extracellular matrix components also provides a reservoir of angiogenic activity that can be mobilized under conditions of stress, such as hypoxia or inflammation.
- In pregnancy, PlGF-2 plays a critical role in placental vascular development. By promoting trophoblast invasion and vascular remodeling, it contributes to the establishment of adequate maternal–fetal blood flow. Dysregulation of PlGF-2, along with other PlGF isoforms, is strongly implicated in pregnancy-related disorders such as preeclampsia and intrauterine growth restriction (IUGR). In these conditions, circulating levels of PlGF (including PlGF-2) are markedly reduced, making it a key biomarker for the diagnosis and monitoring of placental dysfunction.
- Outside of reproduction, PlGF-2 has important implications in cardiovascular, inflammatory, and neoplastic diseases. In ischemic heart disease and peripheral artery disease, PlGF-2 promotes angiogenesis and collateral vessel formation, aiding tissue repair and oxygen delivery. Conversely, in cancer, PlGF-2 can be co-opted by tumors to drive pathological angiogenesis, tumor growth, and metastasis. Elevated PlGF-2 levels have been reported in several cancers, where it supports the recruitment of pro-tumorigenic immune cells and the remodeling of the tumor microenvironment. Similarly, in chronic inflammatory conditions such as atherosclerosis and rheumatoid arthritis, PlGF-2 can exacerbate disease progression by enhancing leukocyte recruitment and neovascularization within inflamed tissues.
- Therapeutically, PlGF-2 is considered both a target and a tool. On one hand, blocking PlGF (including PlGF-2) using neutralizing antibodies or receptor antagonists has shown promise in reducing tumor angiogenesis, ocular neovascular diseases, and chronic inflammation. On the other hand, strategies to harness PlGF-2 for therapeutic angiogenesis are being explored in ischemic cardiovascular and peripheral vascular diseases, where its potent angiogenic capacity could improve tissue repair. The challenge lies in balancing its beneficial regenerative potential with its pathological roles in cancer and inflammation.
