From Blood Islands to Blood Vessels: Morphologic Observations and Expression of Key Molecules during Hyaloid Vascular System Development

McLeod, D. Scott; Hasegawa, Takuya; Baba, Takayuki; Grebe, Rhonda; d'Auriac, Ines Galtier; Merges, Carol; Edwards, Malia M.; Lutty, Gerard A.

doi:10.1167/iovs.12-10140

Cited by 29 publications

(29 citation statements)

References 70 publications

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“…2 A and B ). We focused on RUNX1 for further studies because of its documented roles in EC biology (17–19). Exposure of HRMEC and HUVEC cultures to high glucose induced a 30% increase in RUNX1 protein, whereas osmotic controls had no significant effect in HRMEC and HUVECs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis

Lam

Wong

et al. 2017

Diabetes

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Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world’s working adult population and affects those with type 1 and type 2 diabetes. We identified Runt-related transcription factor 1 (RUNX1) as a gene upregulated in CD31+ vascular endothelial cells obtained from human PDR fibrovascular membranes (FVMs) via transcriptomic analysis. In vitro studies using human retinal microvascular endothelial cells (HRMECs) showed increased RUNX1 RNA and protein expression in response to high glucose, whereas RUNX1 inhibition reduced HRMEC migration, proliferation, and tube formation. Immunohistochemical staining for RUNX1 showed reactivity in vessels of patient-derived FVMs and angiogenic tufts in the retina of mice with oxygen-induced retinopathy, suggesting that RUNX1 upregulation is a hallmark of aberrant retinal angiogenesis. Inhibition of RUNX1 activity with the Ro5–3335 small molecule resulted in a significant reduction of neovascular tufts in oxygen-induced retinopathy, supporting the feasibility of targeting RUNX1 in aberrant retinal angiogenesis.

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Section: Resultsmentioning

confidence: 99%

Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis

Lam

Wong

et al. 2017

Diabetes

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“…While prevailing models suggest that hyaloid growth occurs through angiogenesis (e.g. (Saint-Geniez and D'Amore, 2004), recent data in the human eye suggest that hemo-vasculogenesis may build the hyaloid (McLeod et al, 2012). Our in vivo imaging data support an angiogenic mechanism for hyaloid development in zebrafish, and to our knowledge, these data are the first to demonstrate hyaloid angiogenesis in vivo in any vertebrate system.…”

Section: Discussionmentioning

confidence: 99%

“…The hyaloid network connects to the choroidal network at the annular vessel, located along the anterior aspect of the optic cup, thereby providing drainage from the hyaloid, which contains no veins. The hyaloid vasculature is thought to form via angiogenesis, although recent data from human eyes indicate that the hyaloid system in humans may develop through hemo-vasculogenesis from a pool of hemangioblast precursors (McLeod et al, 2012). In mammals, the hyaloid system regresses during late stages of eye development, concomitant with the formation of the retinal vasculature (reviewed in (Saint-Geniez and D'Amore, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Fate mapping studies in mouse have also demonstrated that both neural crest and mesoderm-derived cells contribute to the hyaloid (Gage et al, 2005). While studies have been performed to characterize the hyaloid in humans (Balazs et al, 1980; McLeod et al, 2012; Zhu et al, 2000), primates (Hamming et al, 1977), mouse (Balazs et al, 1980; Gage et al, 2005; Poche et al, 2009), hamster, rabbit, cow, cat (Balazs et al, 1980) and zebrafish (Alvarez et al, 2007; Kitambi et al, 2009), most of these studies utilized fixed samples and were therefore unable to identify any of the dynamic cellular behaviors that underlie hyaloid formation.…”

Section: Introductionmentioning

confidence: 99%

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In vivo analysis of hyaloid vasculature morphogenesis in zebrafish: A role for the lens in maturation and maintenance of the hyaloid

Hartsock

Lee

Arnold

et al. 2014

Developmental Biology

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Two vascular networks nourish the embryonic eye as it develops - the hyaloid vasculature, located at the anterior of the eye between the retina and lens, and the choroidal vasculature, located at the posterior of the eye, surrounding the optic cup. Little is known about hyaloid development and morphogenesis, however. To begin to identify the morphogenetic underpinnings of hyaloid formation, we utilized in vivo time-lapse confocal imaging to characterize morphogenesis of the zebrafish hyaloid through 5 days post fertilization (dpf). Our data segregate hyaloid formation into three distinct morphogenetic stages: Stage I: Arrival of hyaloid cells at the lens and formation of the hyaloid loop; Stage II: Formation of a branched hyaloid network; Stage III: Refinement of the hyaloid network. Utilizing fixed and dissected tissues, distinct Stage II and Stage III aspects of hyaloid formation were quantified over time. Combining in vivo imaging with microangiography, we demonstrate that the hyaloid system becomes fully enclosed by 5dpf. To begin to identify the molecular and cellular mechanisms underlying hyaloid morphogenesis, we identified a recessive mutation in the mab21l2 gene, and in a subset of mab21l2 mutants the lens does not form. Utilizing these “lens-less” mutants, we determined whether the lens was required for hyaloid morphogenesis. Our data demonstrate that the lens is not required for Stage I of hyaloid formation; however, Stages II and III of hyaloid formation are disrupted in the absence of a lens, supporting a role for the lens in hyaloid maturation and maintenance. Taken together, this study provides a foundation on which the cellular, molecular and embryologic mechanisms underlying hyaloid morphogenesis can be elucidated.

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“…Sprouting angiogenesis is predominant as the mode of development of the retinal vasculature, though some studies opt for vasculogenesis with the formation of blood islands (McLeod et al, 2012; also see Saint-Geniez and D'Amore 2004). The retinal vascular system provides a suitable sample for studies of angiogenesis or vasculogenesis, due to the easy preparation of whole mount preparations for overviewing.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of endothelial nutrient transporters (MCT1 and GLUT1) in the developing eyes of mice

Kishimoto

Takahashi-Iwanaga

et al. 2016

Experimental Eye Research

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The blood-brain barrier in the neonatal brain expresses the monocarboxylate transporter (MCT)-1 rather than the glucose transporter (GLUT)-1, due to the special energy supply during the suckling period. The hyaloid vascular system, consisting of the vasa hyaloidea propria and tunica vasculosa lentis, is a temporary vasculature present only during the early development of mammalian eyes and later regresses. Although the ocular vasculature manifests such a unique developmental process, no information is available concerning the expression of endothelial nutrient transporters in the developing eye. The present immunohistochemical study using whole mount preparations of murine eyes found that the hyaloid vascular system predominantly expressed GLUT1 in the endothelium, in contrast to the brain endothelium.Characteristically, the endothelium in peripheral regions of the neonatal hyaloid vessels displayed a mosaic pattern of MCT1-immunoreactive cells scattered within the GLUT1-expressing endothelium. The proper retinal vessels first developed by sprouting angiogenesis endowed with filopodia, which were absolutely free from the immunoreactivities of GLUT1 and MCT1. The remodeling retinal capillary networks and veins in the surface layer of the retina mainly expressed MCT1 until the weaning period. Immunostaining of MCT1 in the retina revealed fine radicular processes projecting from the endothelium, differing from the MCT1-immunonegative filopodia.These findings suggest that the expression of nutrient transporters in the ocular blood vessels is differentially regulated at a cellular level and that the neonatal eyes provide an interesting model for research on nutrient transporters in the endothelium.

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From Blood Islands to Blood Vessels: Morphologic Observations and Expression of Key Molecules during Hyaloid Vascular System Development

Cited by 29 publications

References 70 publications

Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis

Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis

In vivo analysis of hyaloid vasculature morphogenesis in zebrafish: A role for the lens in maturation and maintenance of the hyaloid

Differential expression of endothelial nutrient transporters (MCT1 and GLUT1) in the developing eyes of mice

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