Placental Growth Factor in Diabetic Retinopathy: Disease-Selective Signaling and Mechanistic Rationale for Targeted Therapy

Chronic hyperglycemia disrupts the retinal neurovascular unit, making diabetic retinopathy (DR) the leading cause of adult vision loss. The hallmarks of DR include pathological angiogenesis, vascular leakage, and neurodegeneration. Although vascular endothelial growth factor A (VEGF-A) is a key mediator of these abnormalities and anti-VEGF therapies remain the standard treatment, many patients exhibit incomplete responses, and these therapies do not adequately address inflammation or fibrosis. Placental growth factor (PlGF), a VEGF family member that selectively binds to VEGFR1, has emerged as an important contributor to retinal neovascularization, vascular dysfunction, barrier breakdown, and microinflammation in DR. Unlike VEGF-A, PlGF modulates distinct responses among retinal neurons, glial cells, and vascular cells, with its abnormal expression closely associated with disease progression from non-proliferative to proliferative DR. This review summarizes the context-dependent functions of PlGF in the diabetic retina, compares PlGF–VEGFR1 signaling with VEGF-A–VEGFR2 pathways, and discusses preclinical and clinical evidence supporting PlGF inhibition as a potential complementary approach to existing anti-VEGF therapy.