The development of fluid transport systems was a key event in the evolution of animals and plants. While within vertebrates branched geometries predominate, the choriocapillaris, which is the microvascular bed that is responsible for the maintenance of the outer retina, has evolved a planar topology. Here we examine the flow and mass transfer properties associated with this unusual geometry. We show that as a result of the form of the choriocapillaris, the blood flow is decomposed into a tessellation of functional vascular segments of various shapes delineated by separation surfaces across which there is no flow, and in the vicinity of which the transport of passive substances is diffusion-limited. The shape of each functional segment is determined by the distribution of arterioles and venules and their respective relative flow rates. We also show that, remarkably, the mass exchange with the outer retina is a function of the shape of each functional segment. In addition to introducing a novel framework in which the structure and function of the metabolite delivery system to the outer retina may be investigated in health and disease, the present work provides a general characterisation of the flow and transfers in multipole Hele-Shaw configurations.

Genome-wide association studies have identified the chromosome 10q26 (Chr10) locus, which contains the age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) genes, as the strongest genetic risk factor for age-related macular degeneration (AMD) [L.G. Fritsche et al., Annu. Rev. Genomics Hum. Genet. 15, 151–171, (2014)]. To date, it has been difficult to assign causality to any specific single nucleotide polymorphism (SNP), haplotype, or gene within this region because of high linkage disequilibrium among the disease-associated variants [J. Jakobsdottir et al. Am. J. Hum. Genet. 77, 389–407 (2005); A. Rivera et al. Hum. Mol. Genet. 14, 3227–3236 (2005)]. Here, we show that HTRA1 messenger RNA (mRNA) is reduced in retinal pigment epithelium (RPE) but not in neural retina or choroid tissues derived from human donors with homozygous risk at the 10q26 locus. This tissue-specific decrease is mediated by the presence of a noncoding, cis-regulatory element overlapping the ARMS2 intron, which contains a potential Lhx2 transcription factor binding site that is disrupted by risk variant rs36212733. HtrA1 protein increases with age in the RPE–Bruch’s membrane (BM) interface in Chr10 nonrisk donors but fails to increase in donors with homozygous risk at the 10q26 locus. We propose that HtrA1, an extracellular chaperone and serine protease, functions to maintain the optimal integrity of the RPE–BM interface during the aging process and that reduced expression of HTRA1 mRNA and protein in Chr10 risk donors impairs this protective function, leading to increased risk of AMD pathogenesis. HtrA1 augmentation, not inhibition, in high-risk patients should be considered as a potential therapy for AMD.

The choriocapillaris is a capillary bed located in a thin layer adjacent to the outer retina and is part of the oxygen delivery system to the photoreceptors of the eye. The blood flow is approximately planar and is serviced by microvessels, which join the choriocapillaris through inlets perpendicular to its plane. Capillaries are densely organised and separated by avascular septal posts, which direct the blood flow. The capillary bed is composed of a juxtaposition of tessellating vascular units called lobules, which are filled and drained independently from each other. A theoretical analysis of the blood flow in an idealised model of a lobule of the choriocapillaris is developed and studied. Lobules are modelled as tessellating polygonal prisms, where the upper and lower surfaces correspond to planar parallel membranes. The septae are modelled as cylinders randomly distributed between the two membranes. Feeding arterioles and draining venules are modelled as inlets and outlets connecting at the lower surface of the prism perpendicularly to the plane of the lobule. An inlet is placed inside the lobule, while an outlet is placed at each of the vertices. The polygonal prism can be formally subdivided into a set of triangular prisms with one inlet and two outlets, each of them located at one of the vertices. The triangular prisms are taken to be isosceles, and are therefore characterised by a vertex angle ω at the inlet and a span L. The flow is viscously dominated, and is investigated in the lubrication limit, in which the characteristic thickness of the prism is much smaller than the diameter of the cylinders. As a result of the geometry, a stagnation point is located midway between the outlets. A separation streamline joins the inlet and the stagnation point. The pressure drop p and the average fluid particle residence time T are analysed as a function of the angle at the inlet ω and the septae volume fraction Φ. When no cylinders are present (Φ = 0), an analytical expression for the pressure field is calculated by conformal mapping. Close to the triangle walls, the flow is quasi-parallel and characterised by a shorter fluid particle residence time. In the vicinity of the stagnation point, the velocity decreases and the residence time diverges logarithmically with the distance to the stagnation streamline. The minimum in pressure drop corresponds to a maximum in residence time, and is obtained for ω = π/2. Asymptotic expressions for the pressure drop and average residence time are formulated in both the limits ω 1 and π − ω 1. The impact of Φ on the flow is characterised by solving the equations for the flow numerically and using the Darwin drift framework. We show that the pressure drop is approximately proportional to 1 + 2Φ for relatively small Φ, and that T is proportional to 1 − Φ regardless of the void fraction or shape of the septae. In the case Φ = 0, the average † Email address for correspondence: moussa.zouache.10@ucl.ac.uk 38 M. A. Zouache, I. Eames and P. J. Luthert residence time equals the volume of ...

The two most common genetic contributors to age-related macular degeneration (AMD), a leading cause of irreversible vision loss worldwide, are variants associated with CFH-CFHR5 on chromosome 1 (Chr1) and ARMS2/HTRA1 on chromosome 10 (Chr10). We sought to determine if risk and protective variants associated with these two loci drive differences in macular retinal thickness prior and subsequent to the onset of clinically observable signs of AMD. We considered 299 individuals (547 eyes) homozygous for risk variants or haplotypes on Chr1 or Chr10 exclusively (Chr1-risk and Chr10-risk, respectively) or homozygous for a neutral haplotype (Chr1-neu), for the protective I62 tagged haplotype (Chr1-prot-I62) or for the protection conferring CFHR1/3 deletion haplotype (Chr1-prot-del) on Chr1 without any risk alleles on Chr10. Among eyes with no clinically observable signs of AMD, the deletion of CFHR1/3, which is strongly protective against this disease, is associated with significantly thicker retinas in the perifovea. When controlling for age, Chr10-risk eyes with early or intermediate AMD have thinner retinas as compared to eyes from the Chr1-risk group with similar disease severity. Our analysis indicates that this difference likely results from distinct biological and disease initiation and progression events associated with Chr1- and Chr10-directed AMD.