Intertidal aquifers host a reactive zone comprised of Fe mineral‐coated sands where fresh and saline groundwaters mix. This zone may significantly influence the export of C, N, P, Fe, and other metals in submarine groundwater discharge (SGD). Toward determining the roles of microbes in Fe and S mineralization, and the interplay of microbiology with geochemistry and physical hydrology, we conducted a biogeochemical study of pore waters at Cape Shores, Delaware. Here, fresh groundwater provides Fe(II), which precipitates as FeIIIOOH predominantly through microbial Fe(II) oxidation. Candidate division OP3 was the dominant microbial group associated with Fe(II)‐ and Fe(III)‐rich regions of the aquifer, suggesting that this uncharacterized phylum may be involved in Fe(II) oxidation. Saline water brings O2, sulfate, and organic C into the intertidal mixing zone. Microbial reduction of sulfate produces sulfide that is transported to the Fe‐mineralized zone leading to the transformation of FeOOH to Fe(II) sulfides. Microbial populations are structured by the availability of chemical species supplied along groundwater flow paths. Seasonal changes in the relative supply of fresh and saline groundwater affect solute fluxes, and therefore, microbial controls on the location and composition of the Fe‐mineralized zone. Ultimately, the composition, extent, and dynamics of the Fe‐mineralized zone will affect the sequestration, affinity, and residence time of solutes bound for export to coastal oceans through SGD.

Purpose PGE2 binds to PGE2 receptors (EP1-4). The purpose of the present study was to investigate the role of the EP4 receptor in angiogenic cell behaviors of retinal Müller cells and retinal microvascular endothelial cells (RMECs) and to assess the efficacy of an EP4 antagonist in rat models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (LCNV). Methods Müller cells derived from COX-2-null mice were treated with increasing concentrations of the EP4 agonist PGE1-OH, and wild-type Müller cells were treated with increasing concentrations of the EP4 antagonist L-161982; VEGF production was assessed. Human RMECs (HRMECs) were treated with increasing concentrations of L-161982, and cell proliferation and tube formation were assessed. Rats subjected to OIR or LCNV were administered L-161982, and the neovascular area was measured. Results COX-2-null mouse Müller cells treated with increasing concentrations of PGE1-OH demonstrated a significant increase in VEGF production (P ≤ 0.0165). Wild-type mouse Müller cells treated with increasing concentrations of L-161982 demonstrated a significant decrease in VEGF production (P ≤ 0.0291). HRMECs treated with increasing concentrations of L-161982 demonstrated a significant reduction in VEGF-induced cell proliferation (P ≤ 0.0033) and tube formation (P < 0.0344). L-161982 treatment significantly reduced pathologic neovascularization in OIR (P < 0.0069) and LCNV (P ≤ 0.0329). Conclusions Preliminary investigation has demonstrated that EP4 activation or inhibition influences the behaviors of two retinal cell types known to play roles in pathologic ocular angiogenesis. These findings suggest that the EP4 receptor may be a valuable therapeutic target in neovascular eye disease.

Retinopathy of prematurity (ROP) is a potentially blinding disease affecting premature infants. ROP is characterized by pathological ocular angiogenesis or retinal neovascularization (NV). Models of ROP have yielded much of what is currently known about physiological and pathological blood vessel growth in the retina. The rat provides a particularly attractive and cost effective model of ROP. The rat model of ROP consistently produces a robust pattern of NV, similar to that seen in humans. This model has been used to study gross aspects of angiogenesis. More recently, it has been used to identify and therapeutically target specific genes and molecular mechanisms involved in the angiogenic cascade. As angiogenesis occurs as a complication of many diseases, knowledge gained from these studies has the potential to impact nonocular angiogenic conditions. This article provides historical perspective on the development and use of the rat model of ROP. Key findings generated through the use of this model are also summarized.

We assessed the effect of topical ketorolac on laser-induced choroidal neovascularization (CNV), measured retinal PGE2 and VEGF levels after laser treatment, and determined the effect of ketorolac on PGE2 and VEGF production. Six laser burns were placed in eyes of rats which then received topical ketorolac 0.4% or artificial tears four times daily until sacrifice. Fluorescein angiography (FA) was performed at 2 and 3 weeks and retinal pigment epithelium-choroid-sclera flat mounts were prepared. The retina and vitreous were isolated at 1, 3, 5, 7, and 14 days after laser treatment and tested for VEGF and PGE2. Additional animals were lasered and treated with topical ketorolac or artificial tears and tested at 3 and 7 days for retinal and vitreous VEGF and PGE2. Ketorolac reduced CNV on FA by 27% at 2 weeks (P < 0.001) and 25% at 3 weeks (P < 0.001). Baseline retina and vitreous PGE2 levels were 29.4 μg/g and 16.5 μg/g respectively, and reached 51.2 μg/g and 26.9 μg/g respectively, 24 h after laser treatment (P < 0.05). Retinal VEGF level was 781 pg/g 24 h after laser treatment and reached 931 pg/g by 7 days (P < 0.01). Ketorolac reduced retinal PGE2 by 35% at 3 days (P < 0.05) and 29% at 7 days (P < 0.001) and retinal VEGF by 31% at 3 days (P = 0.10) and 19% at 7 days (P < 0.001). Topical ketorolac inhibited CNV and suppressed retinal PGE2 and VEGF production.

cPLA(2) liberates arachidonic acid, the substrate for prostaglandin (PG) production by the cyclooxygenase enzymes. PGs can exert a proangiogenic influence by inducing VEGF production and by stimulating angiogenic behaviors in vascular endothelial cells. Inhibition of cPLA(2) inhibits the production of proangiogenic PGs. Thus, cPLA(2) inhibition has a significant influence on pathologic retinal angiogenesis.

The results of this study suggest that MMP-2 plays a predominant role in retinal angiogenesis in both the mouse and rat models of oxygen-induced retinopathy. Furthermore, MMP-2 inhibition may be a viable therapeutic approach for ocular diseases characterized by retinal neovascularization.

Our data support other studies showing that reduction of endoglin expression inhibits retinal NV. Our findings demonstrate that retinal endoglin immunolocalization overlaps with nascent neovascular structures in OIR rats. Therefore, endoglin may serve as a useful predictor of incipient neovascular disease.

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