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Purpose: To determine whether the degree of venous tortuosity is significantly correlated with the aqueous vascular endothelial growth factor (VEGF) concentration in eyes with a central retinal vein occlusion (CRVO)., Methods: We reviewed the medical records of 32 eyes of 32 patients who had macular edema due to a CRVO. All of the patients were examined at the Nagoya University Hospital and were scheduled to receive an intravitreal injection of bevacizumab (IVB) or ranibizumab (IVR) within 12 weeks of the onset of the CRVO to treat the macular edema. Aqueous humor was collected just before the IVB or IVR, and the VEGF concentration was determined by enzyme-linked immunosorbent assay (ELISA). The venous tortuosity index was calculated by dividing the length of the retinal veins by the chord length of the same segment. The correlation between the mean tortuosity index of the inferotemporal and supratemporal branches of the retinal vein and the aqueous VEGF concentration was determined., Results: The mean aqueous VEGF concentration was 384 ± 312 pg/ml with a range of 90 to 1077 pg/ml. The degree of venous tortuosity was significantly correlated with the VEGF concentration in the aqueous. (r = 0.49, P = 0.004), with the foveal thickness (r = 0.40, P = 0.02), and with the best-corrected visual acuity (r = 0.38, P = 0.03)., Conclusions: The significant correlation between the aqueous VEGF concentration and the venous tortuosity indicates that the degree of retinal venous tortuosity can be used to identify eyes that are at a high risk of developing neovascularization.

The vasculature of the central nervous system (CNS) is composed of vascular endothelial and mural cells which interact closely with glial cells and neurons. The development of the CNS vascularisation is a unique process which requires the contribution of specific regulators in addition to the classical angiogenic factors. The egfl7 gene is mainly detected in endothelial cells during physiological and pathological angiogenesis. Egfl7 codes for a secreted protein which predominantly accumulates into the extracellular space where it controls vascular elastin deposition or the Notch pathway. Egfl7 is the host gene of the microRNA miR126 which is also expressed in endothelial cells and which plays major functions during blood vessel development. While the expression of egfl7 and that of miR126 were well described in endothelial cells during development, their pattern of expression during the establishment of the CNS vasculature is still unknown. By analysing the expression of egfl7 and miR126 during mouse retina vascularisation, we observed that while expression of miR126 is detected in all endothelia, egfl7 is initially expressed in all endothelial cells and then is progressively restricted to veins and to their neighbouring capillaries. The recruitment of mural cells around retina arteries coincides with the down-regulation of egfl7 in the arterial endothelial cells, suggesting that this recruitment could be involved in the loss of egfl7 expression in arteries. However, the expression pattern of egfl7 is similar when mural cell recruitment is prevented by the injection of a PDGFRβ blocking antibody, suggesting that vessel maturation is not responsible for egfl7 down-regulation in retinal arteries.

Introduction: C-reactive protein (CRP) levels are associated with cardiovascular disease and systemic inflammation. We assessed whether CRP-associated loci were associated with serum CRP and retinal markers of microvascular disease, in Asian populations., Methods: Genome-wide association analysis (GWAS) for serum CRP was performed in East-Asian Chinese (N = 2,434) and Malays (N = 2,542) and South-Asian Indians (N = 2,538) from Singapore. Leveraging on GWAS data, we assessed, in silico, association levels among the Singaporean datasets for 22 recently identified CRP-associated loci. At loci where directional inconsistencies were observed, quantification of inter-ethnic linkage disequilibrium (LD) difference was determined. Next, we assessed association for a variant at CRP and retinal vessel traits [central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE)] in a total of 24,132 subjects of East-Asian, South-Asian and European ancestry., Results: Serum CRP was associated with SNPs in/near APOE, CRP, HNF1A and LEPR (p-values ≤4.7×10(-8)) after meta-analysis of Singaporean populations. Using a candidate-SNP approach, we further replicated SNPs at 4 additional loci that had been recently identified to be associated with serum CRP (IL6R, GCKR, IL6 and IL1F10) (p-values ≤0.009), in the Singaporean datasets. SNPs from these 8 loci explained 4.05% of variance in serum CRP. Two SNPs (rs2847281 and rs6901250) were detected to be significant (p-value ≤0.036) but with opposite effect directions in the Singaporean populations as compared to original European studies. At these loci we did not detect significant inter-population LD differences. We further did not observe a significant association between CRP variant and CRVE or CRAE levels after meta-analysis of all Singaporean and European datasets (p-value >0.058)., Conclusions: Common variants associated with serum CRP, first detected in primarily European studies, are also associated with CRP levels in East-Asian and South-Asian populations. We did not find a causal link between CRP and retinal measures of microvascular disease.

Purpose: To study the variation in intravascular oxygen saturation (oximetry) during an acute retinal vein occlusion (RVO) using hyperspectral computed tomographic spectroscopy based oximetry measurements., Methods: Thirty rabbits were dilated and anesthetized for experiments. Baseline oximetry measurements were made using a custom-made hyperspectral computed tomographic imaging spectrometer coupled to a fundus camera. RVO were induced using argon green laser following an intravenous injection of Rose Bengal. RVO induction was confirmed by fluorescein angiography. Retinal oximetry measurements were repeated in arterial and venous branches one hour after RVO induction and up to 4 weeks afterwards. Comparison of retinal oximetry before and after vein occlusion was made using the Student T-test., Results: One hour after RVO induction, we observed statistically significant reductions in the intravascular oxygen saturation in temporal retinal arteries (85.1 ± 6.1% vs. 80.6 ± 6.6%; p<0.0001) and veins (71.4 ± 5.5% vs. 64.0 ± 4.7%; p<0.0001). This decrease was reversible in animals that spontaneously recannulated the vein occlusion. There were no statistically significant differences in oxygen saturation in the nasal control arteries and veins before and after temporal vein RVO induction., Conclusions: We demonstrate, for the first time, acute changes in the intravascular oxygen content of retinal vessels 1 hour after RVO. These changes are reversible upon spontaneous recannulation of retinal vessels. This study demonstrates that hyperspectral computer tomographic spectroscopy based oximetry can detect physiological variations in intravascular retinal oxygen saturation. The study also provides the first qualitative and quantitative evidence of the variation in retinal vascular oxygen content directly attributable to an acute retinal vein occlusion.

Vasoregression is a hallmark of vascular eye diseases but the mechanisms involved are still largely unknown. We have recently characterized a rat ciliopathy model which develops primary photoreceptor degeneration and secondary vasoregression. To improve the understanding of secondary vasoregression in retinal neurodegeneration, we used microarray techniques to compare gene expression profiles in this new model before and after retinal vasoregression. Differential gene expression was validated by quantitative RT-PCR, Western blot and immunofluorescence. Of the 157 genes regulated more than twofold, the MHC class II invariant chain CD74 yielded the strongest upregulation, and was allocated to activated microglial cells close to the vessels undergoing vasoregression. Pathway clustering identified genes of the immune system including inflammatory signaling, and components of the complement cascade upregulated during vasoregression. Together, our data suggest that microglial cells involved in retinal immune response participate in the initiation of vasoregression in the retina.

Expression of the new G protein-coupled msr/apj receptor in the mouse embryo is restricted to the endothelial layer of the primary blood vessels and the newly forming heart (Mech. Dev. 84 (1999) 199). During development of the retinal vasculature, the msr/apj gene is not expressed throughout the vascular network, indicating a possible relationship between the localization of expression and the acquisition of arterial or venous identity (Mech. Dev. 110 (2002) 183). Here we first established that retinal expression of ephrin-B2 and its putative receptor EphB4 correlates with arterial and venous phenotype, respectively. Then we analyzed the expression pattern of msr/apj in the retinal vessels at various stages of postnatal development by in situ hybridization. In contrast to the expression of ephrin-B2 or EphB4, msr/apj transcripts can be detected as early as postnatal day P3. From P3 to P12, msr/apj expression in the vascular network is restricted to the venules and the associated capillaries. The msr/apj gene is thus an early and specific marker of the venous phenotype in the retinal vasculature.