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EMBO Mol Med. 2018 Jan;10(1):76-90. doi: 10.15252/emmm.201707966.

Photoreceptor glucose metabolism determines normal retinal vascular growth.

Author information

1
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
2
Section for Ophthalmology, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
3
Merck Research Laboratories, Boston, MA, USA.
4
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
5
Pediatrics, Department of Clinical Sciences, Skåne University Hospital and University of Lund, Lund, Sweden.
6
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA lois.smith@childrens.harvard.edu.

Abstract

The neural cells and factors determining normal vascular growth are not well defined even though vision-threatening neovessel growth, a major cause of blindness in retinopathy of prematurity (ROP) (and diabetic retinopathy), is driven by delayed normal vascular growth. We here examined whether hyperglycemia and low adiponectin (APN) levels delayed normal retinal vascularization, driven primarily by dysregulated photoreceptor metabolism. In premature infants, low APN levels correlated with hyperglycemia and delayed retinal vascular formation. Experimentally in a neonatal mouse model of postnatal hyperglycemia modeling early ROP, hyperglycemia caused photoreceptor dysfunction and delayed neurovascular maturation associated with changes in the APN pathway; recombinant mouse APN or APN receptor agonist AdipoRon treatment normalized vascular growth. APN deficiency decreased retinal mitochondrial metabolic enzyme levels particularly in photoreceptors, suppressed retinal vascular development, and decreased photoreceptor platelet-derived growth factor (Pdgfb). APN pathway activation reversed these effects. Blockade of mitochondrial respiration abolished AdipoRon-induced Pdgfb increase in photoreceptors. Photoreceptor knockdown of Pdgfb delayed retinal vascular formation. Stimulation of the APN pathway might prevent hyperglycemia-associated retinal abnormalities and suppress phase I ROP in premature infants.

KEYWORDS:

adiponectin; hyperglycemia; metabolism; photoreceptor; retinopathy of prematurity

PMID:
29180355
PMCID:
PMC5760850
DOI:
10.15252/emmm.201707966
[Indexed for MEDLINE]
Free PMC Article

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