Placental Growth Factor Inhibition for Choroidal Neovascularization

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family of angiogenesis factors. It has the highest expression level in the endothelium as compared to other VEGF family members and plays an important role in pathological neovascularization. 1 In humans, four isoforms of PlGF exist (PlGF-1 through 4). Mice only express a single isoform of PlGF which is comparable to human PlGF-2. 2 There has been great interest in the physiological function of PlGF. Its global deletion, unlike VEGF-A, is not lethal suggesting minimal role for PlGF during embryonic development. 3 Deletion of a single allele of VEGF-A has significant impact on embryonic development suggesting non-overlapping functions for these factors. The specific functions of the VEGF family members are related to the specificity of these factors for their corresponding cell surface receptors. Although VEGF-A interacts with VEGF receptor-1 (VEGFR-1 also known as flt-1) and VEGF receptor-2 (VEGFR-2 also known as KDR), PlGFs can interact with VEGF-R1 as well as neuropilins. However, PlGF-1 only interacts with VEGFR-1 and not neuropilins. 4 PlGF and other members of the VEGF family are expressed in the retina with distinct regulatory roles during retinal vascular development and regression of the hyaloid vasculature. In addition, their altered expression plays an important role in ischemia mediated retinal neovascularization. 7 Interestingly, only the expression of PlGF is augmented by hyperoxia. 6 The exogenous administration of PlGF-1 and exclusive activation of VEGFR-1 protects retinal vasculature from hyperoxia-mediated vaso-obliteration. 4 Thus, specific targeting and activation of VEGFR-1 may have therapeutic benefit during oxygen-induced ischemic retinopathy. Studies attempting to delineate the physiological function of PlGF have resulted in contradictory reports regarding the role of PlGF in pathological neovascularization with some cancers but not others. It is now somewhat clear that inhibition of PlGF activity using antibodies may be tumor specific and requires functional VEGFR-1 expression. 10 However, not all anti-PlGF antibodies show antagonistic activity, 8 the reason for which remains unclear. In addition, PlGF may synergize with VEGF under some conditions with significant impact on pathological angiogenesis. 3 Studies with PlGF null mice have consistently shown attenuation of choroidal neovascularization (CNV) in the laser model, and antibodies to PlGF or VEGFR-1 are similarly efficacious in inhibiting CNV in this model. The proangiogenic activity of PlGF in this model may be attributed to its function in recruiting macrophages and their proangiogenic programming in exudative AMD. 12 In …