Placenta growth factor (PlGF) is a close homolog of vascular endothelial growth factor (VEGF), shares receptors with VEGF, and stimulates angiogenesis (1). Intravitreous PlGF levels are elevated in proliferative diabetic retinopathy (PDR) (2), but the relationship between PlGF levels and VEGF levels or clinical activity remains unclear. We attempted to ascertain whether intravitreous PlGF levels correlate with VEGF levels or clinical activity in PDR.

We assayed PlGF and VEGF levels in vitreous samples from 50 consecutive patients with PDR (31 patients) and macular hole (nondiabetic control subjects, 19 patients) who underwent pars plana vitrectomy. The PDR stage was classified as active (16 patients) if there were new preretinal capillaries and as quiescent (15 patients) if the vasoproliferation consisted of only large vessels (3, 4). Informed consent was obtained from each patient. The undiluted vitreous samples were collected during the vitrectomy before intraocular infusion. Vitreous PlGF and VEGF concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) for PlGF and VEGF (R&D Systems, Minneapolis, MN) according to the manufacturer’s protocol. The total protein concentration of the vitreous humor was measured using a BCA protein assay kit (Pierce Chemical, Rockford, IL). The Mann-Whitney U test was used to compare vitreous concentrations of PlGF and VEGF. Spearman’s rank correlation test was used to examine correlations.

PlGF and VEGF levels (median range) in PDR (PlGF, 100.6 pg/ml, range 7.6–1,038.6; VEGF 653.9 pg/ml, 9.0–5,423.8) were significantly higher (P > 0.0001) than in the control (PlGF 7.0 pg/ml, 7.0–12.1; VEGF 9.0 pg/ml, 9.0–10.0). Moreover, the differences remained highly significant (P < 0.0001) when the ratio of PlGF and VEGF to protein was considered (PlGF 14.6, 1.5–250.7 vs. 2.6, 1.1–4.1; VEGF 95.5, 2.0–904.0 vs. 3.0, 1.4–5.3) (4,5).

The ratio of PlGF and VEGF to protein in active PDR patients was significantly higher than that in quiescent PDR patients (PlGF 33.5, 2.7–250.7 vs. 11.1, 1.5–35.8, P = 0.0039; VEGF 130.1, 7.8–904.0 vs. 73.9, 2.0–150.3, P = 0.0328).

Intravitreous PlGF levels significantly correlated with intravitreous VEGF levels in both PDR patients (r = 0.824, P < 0.0001) and total subjects (r = 0.857, P < 0.0001).

Neovascularization is the most important event in PDR. PlGF stimulates angiogenesis in vivo (1). PlGF is detected in the fibrovascular membranes of PDR (2), and PlGF mRNA expression significantly increases in retina during diabetic retinopathy (6). In this study, intravitreous PlGF levels were significantly higher in active PDR than in quiescent PDR, suggesting that PlGF is involved in the developing stages of PDR.

PlGF does not directly induce endothelial cell proliferation or vascular permeability but acts indirectly by potentiating the activity of VEGF (7,8). Genetic studies indicate a synergism between PlGF and VEGF in pathological angiogenesis (9). In the present study, intravitreous PlGF levels significantly correlated with VEGF levels. Taken together, these results suggest that PlGF might have a cooperative role with VEGF in the progression of PDR.

Ziche M, Maglione D, Ribatti D, Morbidelli L, Lago CT, Battisti M, Paoletti I, Barra A, Tucci M, Parise G, Vincenti V, Granger H, Viglietto G, Persico MG: Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic.
Lab Invest
Khaliq A, Foreman D, Ahmed A, Weich H, Gregor Z, McLoad D, Boulton M: Increased expression of placenta growth factor in proliferative diabetic retinopathy.
Lab Invest
Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Iwamoto HTMA, Park JE, Nguyen HV, Aiello LM, Ferrara N, King GL: Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders.
N Engl J Med
Katsura Y, Okano T, Noritake M, Kosano H, Nishigori H, Kado S, Matsuoka T: Hepatocyte growth factor in vitreous fluid of patients with proliferative diabetic retinopathy and other retinal disorders.
Diabetes Care
Burgos R, Mateo C, Canton A, Hernandez C, Mesa J, Simo R: Vitreous levels of IGF-1, IGF binding protein 1, and IGF binding protein 3 in proliferative diabetic retinopathy.
Diabetes Care
Spirin KS, Saghizadeh M, Lewin SL, Zardi L, Kenney MC, Ljubimov AV: Basement membrane and growth factor gene expression in normal and diabetic human retinas.
Curr Eye Res
Park JE, Chen HH, Winer J, Houck KA, Ferrara N: Placenta growth factor: potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not Flk-1/KDR.
J Biol Chem
Dull RO, Yuan J, Chang YS, Tarbell J, Jain Rk, Munn LL: Kinetics of placenta growth factor/vascular endothelial growth factor synergy in endothelial hydraulic conductivity and proliferation.
Microvasc Res
Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, Mol MD, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG: Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.
Nat Med

Address correspondence to Yoshinori Mitamura, Department of Ophthalmology, School of Medicine, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: