Abstract
Under normal conditions, the cornea, being the transparent “windscreen” of the eye, is free of both blood and lymphatic vessels. However, various diseases of the eye, like infections, can interfere with the balance between promoting and inhibiting factors, which leads to ingrowth of blood and lymphatic vessels. The newly formed lymphatic vessels increase the risk of graft rejection after subsequent corneal transplantation. Corneal transplantation is one of the most commonly performed transplantations worldwide, with more than 40,000 surgeries per year in Europe. To date, various anti-hem- and anti-lymphangiogenic treatment strategies have been developed specifically for the corneal vascular endothelial growth factor (VEGF) pathway. Currently, however, no treatment strategies are clinically available to specifically modulate lymphangiogenesis. In this review, we will give an overview about endogenous regulators of hem- and lymphangiogenesis and discuss potential new strategies for targeting pathological lymphangiogenesis. Furthermore, we will review recently identified modulators and demonstrate that the cornea is a suitable model for the identification of novel endogenous modulators of lymphangiogenesis. The identification of novel modulators of lymphangiogenesis and a better understanding of the signaling pathways involved will contribute to the development of new therapeutic targets for the treatment of pathological lymphangiogenesis. This, in turn, will improve graft rejection, not only for the cornea.
Highlights
IntroductionThe cornea is a well-established model to analyze the mechanism underlying (lymph)angiogenesis
The cornea is a well-established model to analyze the mechanism underlyingangiogenesis
These endogenous antiangiogenic factors can be categorized into endostatin/endostatin analogues, plasminogen/serine protease inhibitors, thrombospondin-1, -2 and soluble vascular endothelial growth factor (VEGF) receptors [28,29,30,31,32]
Summary
The cornea is a well-established model to analyze the mechanism underlying (lymph)angiogenesis. The pro-angiogenic factor VEGF-A has been shown to be capable of inducing lymphangiogenesis This effect can be mediated either indirectly by the recruitment of VEGFR-1 positive macrophages, which secrete VEGF-C and D, or directly by proliferative action on the lymphatic endothelial cells [13,14,15]. Endogenous inhibitors play an important regulatory role in preserving the angiogenic privilege and inhibiting and regressing blood and lymphatic vessels induced by minor vascular stimuli These endogenous antiangiogenic factors can be categorized into endostatin/endostatin analogues (endostatin, arresten, and tumstatin), plasminogen/serine protease inhibitors (angiostatin and pigment epithelial-derived factor [PEDF]), thrombospondin-1, -2 and soluble VEGF receptors [28,29,30,31,32]. The identification of novel endogenous regulators contributes to a better understanding of the role of angiogenesis and lymphangiogenesis in corneal transplants, which subsequently has the potential to reduce graft rejection rates
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