Abstract

FR.14.01

Mechanisms of endothelial guidance in development and disease

Gerhardt H. 
Vascular Biology Laboratory, London Research Institute – Cancer Research, London/UK

Developmental angiogenesis in the retina is a guided process. Endothelial tip cells navigate along retinal astrocytes using filopodia^1,2. Astrocytes produce matrix components and VEGF-A gradients, providing both substrate and chemotactic force for guided migration of endothelial tip cells 2. The VEGF-A gradient depends on heparin-binding VEGF isoforms, which include the C-terminal retention motif encoded by exons 6 and 7³. Disruption of endogenous VEGF-A gradients results in loss of guided tip cell migration. The trailing stalk cells proliferate upon VEGF-A stimulation. Disrupted VEGF-A gradients reach further into the plexus causing widespread stalk cell proliferation and increased vessel diameter⁴. Thus VEGF-A gradients balance guided tip cell migration and stalk cell proliferation to regulate vascular patterning. Retinal neo-vascularization processes frequently cause vasculopathies and blindness. Evidence from both mouse models and clinical studies suggested that matrix metalloproteases (MMPs) contribute to pathological neo-vascularization, however, the mechanism remained unclear. Here we identify cleavage of the heparin-binding domain of VEGF-A by MMPs as the major culprit in retinal vasculopathy. In a mouse model of oxygen induced retinopathy, MMP mediated cleavage of VEGF-A caused loss of local VEGF-A retention, which in turn abrogated guided revascularization, but promoted widespread endothelial proliferation. Inhibition of macrophage infiltration, MMP activity and deficiency in macrophage derived MMP-12, all led to substantially restored guided revascularization and reduced pre-retinal vessel formation. Gain of function studies illustrated that MMPs activity is sufficient to cause vascular abnormalities during developmental angiogenesis. Finally, we found a close correlation of human retinal vasculopathy with VEGF-A cleavage and high intravitreal levels of MMPs, together providing a strong concept for MMP dependent cleavage of VEGF-A and loss of guided revascularization as the mechanism of retinal vasculopathy in man and mouse.
1 M. I. Dorrell, E. Aguilar, and M. Friedlander, Invest Ophthalmol Vis Sci 43 (11), 3500 (2002).
2 H. Gerhardt, M. Golding, M. Fruttiger et al., J Cell Biol 161 (6), 1163 (2003).
3 C. Ruhrberg, H. Gerhardt, M. Golding et al., Genes Dev 16 (20), 2684 (2002).
4 C. Ruhrberg, Bioessays 25 (11), 1052 (2003).

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