The mouse retina has been used extensively over the past decades to study both physiologic and pathologic angiogenesis. Over time, various mouse retina models have evolved into well-characterized and robust tools for in vivo angiogenesis research. This article is a review of the angiogenic development of the mouse retina and a discussion of some of the most widely used vascular disease models. From the multitude of studies performed in the mouse retina, a selection of representative works is discussed in more detail regarding their role in advancing the understanding of both the ocular and general mechanisms of angiogenesis.

Many sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. These diseases include retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle age affecting over 4 million people in the United States. We studied the influence of ω-3-and ω-6-polyunsaturated fatty acids (PUFAs) on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy 1 . We show that increasing ω-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissionsCorrespondence should be addressed to L.E.H.S. (lois.smith@childrens.harvard.edu).. Supplementary information is available on the Nature Medicine website. COMPETING INTERESTS STATEMENTThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http:// www.nature.com/naturemedicine/. HHS Public AccessAuthor manuscript Nat Med. Author manuscript; available in PMC 2015 July 05. Published in final edited form as:Nat Med. 2007 July ; 13(7): 868-873. doi:10.1038/nm1591. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The bioactive ω-3-PUFA-derived mediators neuroprotectinD1, resolvinD1 and resolvinE1 also potently protected against neovascularization. The protective effect of ω-3-PUFAs and their bioactive metabolites was mediated, in part, through suppression of tumor necrosis factor-α. This inflammatory cytokine was found in a subset of microglia that was closely associated with retinal vessels. These findings indicate that increasing the sources of ω-3-PUFA or their bioactive products reduces pathological angiogenesis. Western diets are often deficient in ω-3-PUFA, and premature infants lack the important transfer from the mother to the infant of ω-3-PUFA that normally occurs in the third trimester of pregnancy 2 . Supplementing ω-3-PUFA intake may be of benefit in preventing retinopathy.Ocular neovascularization is the most common cause of blindness in all age groups: retinopathy of prematurity in children, diabetic retinopathy in working-age adults and agerelated macular degeneration in the elderly. In principle, destructive angiogenesis in the eye can be ameliorated by either direct inhibition of neovascularization or by controlling vessel loss in order to reduce the hypoxic stimulus that drives neovascularization. Retinopathy is modeled in the mouse eye with oxygen-induced vessel loss, which precipitates hypoxiainduced retinopathy, allowing for assessment of retinal vessel loss, vessel regrowth after injury and pathological angiogenesis 1 .The role of lipids in angiogenesis is just beginning to be defined 3,4 . The major polyunsaturated fatty acids (PUFA) found in the retina a...

These results indicate that persistent low serum concentrations of IGF-I after premature birth are associated with later development of ROP and other complications of prematurity. IGF-I is at least as strong a determinant of risk for ROP as postmenstrual age at birth and birth weight.

To investigate whether postnatal growth and development influence retinopathy of prematurity (ROP) and may be included in screening for ROP. Design: We developed an algorithm to predict for individual infants the risk of later ROP development requiring treatment based on the postnatal longitudinal systemic factors of insulin-like growth factor I (IGF-I) level, IGF binding protein 3 level, and postnatal weight gain. We developed the algorithm based on 79 preterm infants considered at risk for ROP by standard criteria (gestational age, 23.6-31.7 weeks) in a longitudinal study measuring weight gain and serum IGF-I and IGF binding protein 3 levels weekly from birth until discharge from the hospital. We monitored deviations from reference models for weight and IGF-I level (preterm children who developed no or minimal ROP) to detect indications for

The weight, insulin-like growth factor, neonatal retinopathy of prematurity algorithm detected early 100% of infants who developed retinopathy of prematurity requiring treatment and correctly predicted the majority who did not require treatment. With this simple postnatal evaluation, costly stressful eye examinations can be markedly reduced (approximately 75% of infants). In addition, early identification of children at risk may lead to the initiation of interventions and possibly prevent sight-threatening retinopathy of prematurity.

To validate in a prospective study the surveillance algorithm WINROP for detecting infants at risk for proliferative retinopathy of prematurity (ROP).Methods: Fifty preterm infants with a mean gestational age of 26 weeks were included. In the first step of WINROP, weekly measures of body weight and serum insulinlike growth factor I (IGF-I) level from birth until postmenstrual age 36 weeks are entered and compared with expected development. If any of the variables show a negative deviation to a certain degree, an alarm is given. In the second step, gestational age, birth weight, and IGF binding protein 3 level are entered. Results:The WINROP algorithm identified all children (100% sensitivity) who were diagnosed with proliferative ROP 1.1 to 21.6 weeks later. No infants with no alarm or with alarm at low risk developed proliferative ROP. Alarm at high risk before postmenstrual age 32 weeks was given for 22 of 50 infants (44%); 9 of these infants developed proliferative ROP (54% specificity), of whom 8 were treated. Conclusion:The WINROP algorithm may be a useful tool for modification of ROP screening.

SUMMARYBackground & aimsThe purpose of the study was to compare the effects of the parenteral emulsion SMOFlipid®, with 15% fish oil, with Clinoleic® on retinopathy of prematurity (ROP) and other morbidities and growth, and to compare their impact on longitudinal serum levels of fatty acids. Retinopathy of prematurity, other morbidity and growth were correlated with each parenteral lipid supplement.MethodsNinety infants born at gestational age <28 weeks were randomized to treatment with SMO-Flipid® or Clinoleic®. Two thirds (66%) of the infants received parenteral nutrition for up to 14 days birth (median 8, range 2–14 days), and additional 25% of the infants received for up to 28 days after birth (median 21, range 15–28 days). Cord blood samples and then venous blood samples were obtained at ages 1, 7, 14, and 28 days and at postmenstrual age (PMA) 32, 36, and 40 weeks. Breastmilk was collected at postnatal day 7, and at PMA 32 and 40 weeks. Serum phospholipid and breastmilk total fatty acids were analyzed by gas chromatography–mass spectrometry. Treatment groups were compared with regard to ROP, bronchopulmonary dysplasia, necrotizing enterocolitis, patent ductus arteriosus sepsis and growth between birth and 36 weeks.ResultsInfants on SMOFlipid® had higher fractions of omega-3 LCPUFA eicosapentaenoic acid (EPA) and slightly higher omega-3 LCPUFA docosahexaenoic acid (DHA) fraction and a decreased arachidonic acid (AA) to DHA ratio from one week after birth up to 32 postmenstrual weeks compared to infants on Clinoleic®. Treatment groups did not differ in morbidities or growth.ConclusionSupplementation with SMOFlipid® containing 15% fish oil during parenteral nutrition increased EPA substantially, DHA marginally, reduced AA and decreased AA to DHA ratio. It did not reduce morbidity or affect growth. Since extremely preterm infants accumulate a large deficit of DHA and AA, studies on more prolonged or different levels of DHA and AA supplementation are warranted.

Poor postnatal growth after preterm birth does not match the normal rapid growth in utero and is associated with preterm morbidities. Insulin‐like growth factor 1 (IGF‐1) axis is the major hormonal mediator of growth in utero, and levels of IGF‐1 are often very low after preterm birth. We reviewed the role of IGF‐1 in foetal development and the corresponding preterm perinatal period to highlight the potential clinical importance of IGF‐1 deficiency in preterm morbidities.ConclusionThere is a rationale for clinical trials to evaluate the potential benefits of IGF‐1 replacement in very preterm infants.