{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPlacental growth factor (PGF) is a versatile member of the vascular endothelial growth factor family that, through binding to VEGFR‐1 and related receptors, plays central roles in tumor angiogenesis, invasion, and abnormal vascular remodeling. In several cancer models – including brain tumors, medulloblastoma, ovarian, gallbladder, and small‐cell lung cancers – PGF not only promotes neovascularization but also directly supports tumor cell survival and metastasis through autocrine/paracrine signaling. This proangiogenic activity, coupled with its ability to modulate inflammatory cues within the tumor microenvironment, makes PGF a pivotal mediator of aberrant tumor vascularization and a potential target for anticancer therapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the setting of pregnancy, PGF is integral to placental development and vascular remodeling. Its balanced expression underlies normal uteroplacental angiogenesis, whereas diminished maternal circulating PGF – often in concert with elevated soluble VEGFR‐1 – is associated with conditions such as preeclampsia, placental insufficiency, and intrauterine growth restriction. Altered levels of PGF have been used not only to discriminate between placental‐mediated fetal compromise and constitutionally small fetuses but also as a predictive biomarker for adverse maternal–fetal outcomes. Moreover, PGF secreted by invasive cytotrophoblasts appears to facilitate the transformation of uterine vessels during implantation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in neovascularization and placental function, PGF contributes to tissue regeneration and inflammation by modulating the recruitment and activation of progenitor and stem cells. Experiments have shown that PGF signals through VEGFR‐1 on bone marrow–derived cells to promote hematopoietic recovery and osteogenesis, and it exhibits chemotactic effects on mesenchymal progenitors during endochondral bone formation. In addition, PGF participates in endothelial differentiation in stem cell populations and can influence barrier function in ocular tissues—a finding of particular relevance to conditions such as diabetic retinopathy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn systemic inflammatory conditions such as sepsis, PGF is up‐regulated in a time‐dependent manner and contributes to vascular permeability, cardiac dysfunction, and overall mortality. Therapeutic strategies aimed at neutralizing VEGF family ligands through decoy receptors (such as sFlt‐1) have been shown to mitigate the deleterious effects associated with the surge of these factors during sepsis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, in the context of hematologic and vascular disorders—including sickle cell disease, pulmonary hypertension, and inflammatory arthritis—PGF produced by erythroid or endothelial cells amplifies inflammatory cascades and vasoactive responses. PGF has been implicated in upregulating cytokine and chemokine expression, inducing endothelin‐1 production, and modulating monocyte activation, thereby linking hemolytic stress to vascular dysfunction and atherosclerotic changes. These observations underscore the potential of targeting PGF‐mediated pathways to ameliorate vascular inflammation and end-organ damage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "39", "end_ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Charlotte Rolny, Massimiliano Mazzone, Sònia Tugues, et al. 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