How PEDF prevents angiogenesis: a hypothesized pathway

Summary

Pigment epithelium-derived factor (PEDF) is a multiple functional protein, coded by the serine proteinase inhibitor, clade F, member 1 (SERPINF1) gene, which has both anti-angiogenic activity and neurotrophic activity at the same time. Its antiangiogenic activity in the mammalian eye is the most potent known at this time. However, the mechanism(s) by which PEDF works in vivo is still uncertain. Some observations suggest that PEDF can simultaneously inhibit the migration and proliferation induced by vascular endothelial growth factor (VEGF), and then further inhibits angiogenesis by interacting with specific cell surface receptors, but no such receptor has been reported to date. Here we propose a hypothesis that PEDF exerts its function by binding with intergrins. Intergrin can therefore serve as the receptor of PEDF.

Introduction

Angiogenesis, the process in which new capillaries form by sprouting from pre-existing ones, occurs normally during embryogenesis and pathologically in tumor growth, diabetic retinopathy, wound healing, psoriasis and rheumatoid arthritis [1], [2], [3], [4], [5], [6], [7], [8]. Generally, angiogenesis is exquisitely controlled in most healthy tissues through a finely tuned balance between pro- and anti-angiogenic factors.

Pathogenic angiogenesis plays an important role in disease progression. It is well known that tumors cannot grow beyond 2–3 mm in diameter without forming new blood vessels. Not restricted to tumors, the neovascularization occurring in diabetic retinopathy threatens the visions of more than 7 million people in the USA alone [1]. Actually, tumor and diabetes are the two most threatening diseases for human health. The ability to control neovascularization would offer a unique opportunity to impact a wide variety of physiological and pathological functions. Thus, preventing neovascularization becomes a fascinating goal for both tumor and diabetic therapy [8], [9], [10], [11], [12], [13], [14]. Developing antiangiogenic factors is becoming a more and more attractive approach for the therapy of tumor, diabetic retinopathies, and other neovascularization-related diseases.

Pigment epithelium-derived factor (PEDF), a 418-amino acid 50 KDa glycoprotein first identified in 1987 by Tombran-Tink and Johnson in conditioned medium from fetal human retinal pigment epithelium (RPE) cell culture, is among the most potent natural antiangiogenic factors, as it specifically inhibits both the migration and proliferation of endothelial cells [15]. The antiangiogenic activity of PEDF is selective because it is effective against newly forming vessels but spares existing ones, and it is reversible. In specific, as an effective anti-angiogenic factor for clinic purposes, PEDF has the following advantages:first, it is not expected to activate drug-resistance genes, and thus offers the potential for effective long-term anti-angiogenic therapy. Second, due to its tolerance in the body, it is unlikely to produce the toxic side effects of synthetic inhibitors. Finally, given its neurotrophic activity, PEDF has the additional advantage of preserving neurons from the damage often caused by vascular disease of the nervous system. In light of PEDFs great promise for anti-angiogenesis, understanding its fundamental mechanism holds the promise of effective therapeutic approaches for treating neovascularization-related diseases.

Some researchers have proposed that maintaining a balance between the pro and anti-angiogenic factors is critical for the regulation of angiogenesis [16]. The expression and the role of angiogenic factors in retinal neovascularization have been well established. Normal angiogenesis requires the coordination of growth factor receptors and integrins, leading to the activation of down stream signals in endothelial cells [17]. Although integrins and growth factor receptors can independently propagate intracellular signals [18], [19], [20], it appears that a synergy between signals initiated by the extracellular matrix (ECM) and growth factors enhances their separately induced angiogenesis [20]. In addition, protein phosphatases such as protein tyrosine phosphatase (PTP) and protein kinases like FAK, Akt, Src, and MAPK play key roles in the cross-talk between the growth factor and integrin pathways [20]. Thus, there are two possible means to inhibit angiogenesis: one is to target the receptors of growth factors; the other is to disrupt the activation of integrin. PEDF is the most potential natural antiangiogenic factor found up to now [15]. However, how it is that PEDF inhibits new blood vessels formation has remained uncertain. Some evidence has indicated that PEDF can inhibit the migration, proliferation, and even permeability induced by VEGF, in vitro or in vivo, and thereby inhibit angiogenesis by interacting with specific cell surface receptors [21], [22], however, no such receptor has been reported to date.