{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, vascular endothelial growth factor‐D (VEGF‑D) is synthesized as a full‐length, inactive precursor that undergoes precise proteolytic processing to yield a mature form exhibiting dramatically enhanced affinity for its receptors VEGFR‑2 and VEGFR‑3. Such processing – mediated by enzymes including plasmin, proprotein convertases, kallikrein‑related peptidase 3, and even cathepsin D – removes flanking NH₂‐ and COOH‐terminal propeptides and exposes critical structural motifs (for example, the N‑terminal α‑helix) that govern both receptor specificity and potency. Mutational studies further indicate that subtle changes within this region can markedly augment VEGFR‑3 activation and potentiate lymphatic sprouting, underscoring the importance of posttranslational processing in dictating VEGF‑D’s bioactivity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its activation by proteolysis, VEGF‑D exerts its biological effects through specific receptor interactions and accessory associations that modulate cellular behavior. It not only binds the conventional tyrosine kinase receptors VEGFR‑2 and VEGFR‑3 but also partakes in signaling complexes with molecules such as neuropilin‑2 and integrin α9β1, thereby facilitating endothelial cell adhesion and directional migration. In addition, VEGF‑D contributes to nonvascular functions by promoting osteoblast differentiation and mineralization and by enhancing tumor cell invasive responses – for example, in chondrosarcoma cells under fluid shear conditions – via downstream pathways that include PI3‑kinase, MAP kinases, and mTOR‐mediated signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn diverse pathological and physiological contexts, VEGF‑D is recognized as a pivotal mediator of both angiogenesis and lymphangiogenesis with substantial clinical and prognostic implications. Elevated or aberrant VEGF‑D expression – detected in ovarian, thyroid, cervical, melanoma, breast, prostate, and even certain lung and renal carcinomas, as well as in tissues such as skeletal muscle – is frequently associated with enhanced lymphatic vessel formation, lymph node metastasis, and adverse clinical outcomes, although context‑dependent variations exist (for example, in early lung adenocarcinoma higher VEGF‑D levels have been linked to reduced metastasis and improved survival). Moreover, VEGF‑D expression is intricately regulated by multiple signaling pathways, including TGF‑β1, β‑catenin, and CCR7, which together integrate environmental cues to modulate tumor progression, tissue remodeling, and even stem cell differentiation. Collectively, these studies underscore VEGF‑D’s multifaceted biological roles and its potential as both a biomarker and therapeutic target in diseases characterized by pathological vascular remodeling and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Tuomas T Rissanen, Johanna E Markkanen, Marcin Gruchala, et al. 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