Background:

During retinal vascularization, growth of different cell populations is linked via a growth factor cascade. In particular, the reciprocal feedback between astrocytes, pericytes and endothelial cells is crucial for proper radial patterning. Natriuretic peptides (ANP and BNP) and their shared cGMP-forming guanylyl cyclase A (GC-A) receptor are expressed by different retinal vascular and neighboring cells, suggesting local modulatory actions on vessel growth and/or permeability.

Methods:

We compared physiological postnatal retinal vascularization in mice with global (GC-A KO) or conditional, endothelial-restricted deletion of GC-A (EC GC-A KO) and respective control mice. In addition, we studied pathological neoangiogenesis in oxygen-induced retinopathy (OIR), a disease model for diabetic retinopathy and retinopathy of prematurity.

Results:

Both 5 and 7 days after birth, physiological vasculogenesis was markedly retarded in GC-A KO as compared to wildtype control mice by almost 50%. However, the number of filopodia of endothelial tip cells at the leading edge of the vascular sprouts was not different between genotypes. In contrast, pathological neoangiogenesis was severely enhanced in GC-A KO mice. Notably, EC GC-A KO mice did not resemble these phenotypes.

Conclusions:

NPs, via GC-A, exert dual actions on retinal angiogenesis: stimulation of physiological vascularization, and attenuation of pathological, hypoxia-driven neovascularization. These effects are not mediated by endothelial cells. Our future studies will be directed to dissect the role of retinal astrocytes and pericytes in the protective angiogenic actions of the NP/GC-A system. Supported by SFB 688.