Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization.

PURPOSE VEGF has been shown to be necessary, but not sufficient alone, for the development of subretinal pathologic angiogenesis. In the current study, the influence of placental growth factor (PlGF), a member of the VEGF family, in human and experimental choroidal neovascularization (CNV) was investigated. METHODS The presence of VEGF family member mRNA was evaluated by RT-PCR in neovascular membranes extracted during surgery. The spatial and temporal pattern of VEGF isoforms and PlGF mRNA expression were explored by using the laser capture catapulting technique and RT-PCR in a murine laser-induced model and in vitro. PlGF expression was also studied in human donor eyes. The influence of endogenous PlGF was evaluated in deficient mice (PlGF(-/-)) and by antibody-mediated neutralization of the PlGF receptor. RESULTS Human neovascular membranes consistently expressed VEGF-A, -B, and -C; PlGF; and VEGFR-1 and -2. The VEGF(120) isoform mRNA was primarily induced in early stages of angiogenesis in vivo and in vitro. PlGF mRNA expression was present in the intact choroid and significantly upregulated during the course of experimental CNV. Both deficient PlGF expression in PlGF(-/-) mice and PlGF receptor neutralization in wild-type mice prevented the development of choroidal neovascularization induced by laser. CONCLUSIONS These observations demonstrate the participation of PlGF in experimental CNV. They identify therefore PlGF as an additional promising target for ocular antiangiogenic strategies.

[1]  M. P. Hartmann,et al.  Basic fibroblast growth factor experimentally induced choroidal angiogenesis in the minipig. , 1994, Current eye research.

[2]  J. Winer,et al.  Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. , 1994, The Journal of biological chemistry.

[3]  Lois E. H. Smith,et al.  Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[4]  E. Keshet,et al.  Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[5]  J. Flanagan,et al.  Heterodimers of Placenta Growth Factor/Vascular Endothelial Growth Factor , 1996, The Journal of Biological Chemistry.

[6]  S. Seregard,et al.  Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. , 1996, Investigative ophthalmology & visual science.

[7]  P. Campochiaro,et al.  Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. , 1997, The American journal of pathology.

[8]  H. Granger,et al.  Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[9]  Harold E. Dvorak,et al.  Angiogenesis: a Dynamic Balance of Stimulators and Inhibitors , 1997, Thrombosis and Haemostasis.

[10]  L. Aiello,et al.  Vascular endothelial growth factor in ocular neovascularization and proliferative diabetic retinopathy. , 1997, Diabetes/metabolism reviews.

[11]  M. Boulton,et al.  Increased expression of placenta growth factor in proliferative diabetic retinopathy. , 1998, Laboratory investigation; a journal of technical methods and pathology.

[12]  M. Cooper,et al.  Vascular endothelial growth factor and its receptors in control and diabetic rat eyes. , 1998, Laboratory investigation; a journal of technical methods and pathology.

[13]  Alan W. Stitt,et al.  Expression of the VEGF gene family during retinal vaso-obliteration and hypoxia. , 1999, Biochemical and biophysical research communications.

[14]  T. Otsuji,et al.  Expression of vascular endothelial growth factor and its receptor (KDR/flk-1) mRNA in experimental choroidal neovascularization. , 1999, Current eye research.

[15]  Ivana K. Kim,et al.  Constitutive expression of VEGF, VEGFR-1, and VEGFR-2 in normal eyes. , 1999, Investigative ophthalmology & visual science.

[16]  G. Neufeld,et al.  Vascular endothelial growth factor (VEGF) and its receptors , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[17]  A. Eggert,et al.  High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  Stanley J. Wiegand,et al.  Vascular-specific growth factors and blood vessel formation , 2000, Nature.

[19]  I J Constable,et al.  Overexpression of vascular endothelial growth factor (VEGF) in the retinal pigment epithelium leads to the development of choroidal neovascularization. , 2000, The American journal of pathology.

[20]  J L Edelman,et al.  Quantitative image analysis of laser-induced choroidal neovascularization in rat. , 2000, Experimental eye research.

[21]  P. Campochiaro,et al.  Retinal and choroidal neovascularization , 2000, Journal of cellular physiology.

[22]  P. Campochiaro,et al.  Inhibition of choroidal neovascularization by intravenous injection of adenoviral vectors expressing secretable endostatin. , 2001, The American journal of pathology.

[23]  R. D'Amato,et al.  Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium. , 2001, The American journal of pathology.

[24]  Peter Bohlen,et al.  Complete inhibition of vascular endothelial growth factor (VEGF) activities with a bifunctional diabody directed against both VEGF kinase receptors, fms-like tyrosine kinase receptor and kinase insert domain-containing receptor. , 2001, Cancer research.

[25]  J. Rakic,et al.  Influence of plasminogen activator inhibitor type 1 on choroidal neovascularization. , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  M. Gillies,et al.  Immunological and Aetiological Aspects of Macular Degeneration , 2001, Progress in Retinal and Eye Research.

[27]  Till Acker,et al.  Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions , 2001, Nature Medicine.

[28]  Robert F. Mullins,et al.  An Integrated Hypothesis That Considers Drusen as Biomarkers of Immune-Mediated Processes at the RPE-Bruch's Membrane Interface in Aging and Age-Related Macular Degeneration , 2001, Progress in Retinal and Eye Research.

[29]  I. Morita,et al.  Novel mechanism for age‐related macular degeneration: An equilibrium shift between the angiogenesis factors VEGF and PEDF , 2001, Journal of cellular physiology.

[30]  M. Persico Placenta Growth Factor , 2001 .

[31]  Joan W. Miller,et al.  Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. , 2002, Archives of ophthalmology.

[32]  Lawrence A. Yannuzzi,et al.  PRECLINICAL AND PHASE 1A CLINICAL EVALUATION OF AN ANTI-VEGF PEGYLATED APTAMER (EYE001) FOR THE TREATMENT OF EXUDATIVE AGE-RELATED MACULAR DEGENERATION , 2002, Retina.

[33]  Thomas J. Liesegang,et al.  An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration.Hageman GS,∗ Luthert PJ, Chong NHV, Johnson LV, Anderson DH, Mullins RF. Prog Ret Eye Res 2001:20:705–732. , 2002 .

[34]  A. Luttun,et al.  Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1 , 2002, Nature Medicine.

[35]  H. Grossniklaus Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Grant MB, ∗ May WS, Caballero S, Brown GAJ, Guthrie SM, Mames RN, Byrne BJ, Vaught T, Spoerri PE, Peck AB, Scott EW. Nat Med 2002;6:607-612. , 2002 .

[36]  P. Rosenstiel,et al.  Erythropoietin and VEGF promote neural outgrowth from retinal explants in postnatal rats. , 2002, Investigative ophthalmology & visual science.

[37]  Carine Munaut,et al.  Matrix metalloproteinase-9 contributes to choroidal neovascularization. , 2002, The American journal of pathology.

[38]  Y. Ogura,et al.  Vascular endothelial growth factor family and receptor expression in human choroidal neovascular membranes. , 2002, Microvascular research.

[39]  A. Ljubimov,et al.  Effects of angiogenic growth factor combinations on retinal endothelial cells. , 2002, Experimental eye research.

[40]  E. Scott,et al.  Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization , 2002, Nature Medicine.

[41]  Joan W. Miller,et al.  Expression of pigment epithelium-derived factor in experimental choroidal neovascularization. , 2002, Investigative ophthalmology & visual science.

[42]  L. Devy,et al.  The pro‐ or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[43]  M. Komada,et al.  Vascular endothelial growth factor expression in choroidal neovascularization in rats , 1997, Graefe's Archive for Clinical and Experimental Ophthalmology.