Dataset Information

Mitochondrial control of hypoxia-induced pathological retinal angiogenesis

ABSTRACT: Objective: Pathological retinal angiogenesis is vision threatening. In mouse oxygen-induced retinopathy (OIR) we sought to define mitochondrial respiration changes longitudinally during hyperoxia-induced vessel loss and with hypoxia-induced neovascularization (NV), and test interventions to address those changes to prevent NV. Methods: OIR was induced in C57BL/6J mice and retinal vasculature was examined at maximum neovessel formation. We assessed total proteome change and the ratio of mitochondrial/nuclear DNA copy numbers (mtDNA/nDNA) of OIR vs. control retinas, and mitochondrial oxygen consumption rates (OCR) in ex vivo OIR vs. control retinas (BaroFuse). Pyruvate vs. vehicle control was supplemented in OIR mice either prior to or during neovessel formation. Results: In OIR vs. control retinas proteomics identified decreased retinal mitochondrial respiration and synaptic formation pathway proteins at peak neovascularization. mtDNA/nDNA was decreased during hypoxia-induced neovessel growth (as was OCR) suggesting impaired mitochondrial respiration. Pyruvate administration during but not prior to neovessel formation (in line with compromised mitochondrial activity) suppressed NV in vivo. Conclusions: Mitochondrial energetics are suppressed during retinal NV in OIR. Appropriately timed supplementation of energy substrates (pyruvate) may be a novel approach in neovascular retinal diseases.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Retina

DISEASE(S): Retinopathy Of Prematurity

SUBMITTER: Zhongjie Fu

LAB HEAD: Zhongjie Fu

PROVIDER: PXD051410 | Pride | 2025-05-06

REPOSITORIES: Pride

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			Action	DRS
	19350_JM8550_tc_1003_F1.mzid.gz	Mzid
	19351_JM8551_tc_1003_F2.mzid.gz	Mzid
	19352_JM8552_tc_1003_F3.mzid.gz	Mzid
	19353_JM8553_tc_1003_F4.mzid.gz	Mzid
	19354_JM8554_tc_1003_F5.mzid.gz	Mzid

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Mitochondrial control of hypoxia-induced pathological retinal angiogenesis.

Yagi Hitomi H Boeck Myriam M Nian Shen S Neilsen Katherine K Wang Chaomei C Lee Jeff J Zeng Yan Y Grumbine Matthew M Sweet Ian R IR Kasai Taku T Negishi Kazuno K Singh Sasha A SA Aikawa Masanori M Hellström Ann A Smith Lois E H LEH Fu Zhongjie Z

Angiogenesis 20240803 4

<h4>Objective</h4>Pathological retinal neovascularization is vision-threatening. In mouse oxygen-induced retinopathy (OIR) we sought to define mitochondrial respiration changes longitudinally during hyperoxia-induced vessel loss and hypoxia-induced neovascularization, and to test interventions addressing those changes to prevent neovascularization.<h4>Methods</h4>OIR was induced in C57BL/6J mice and retinal vasculature was examined at maximum neovessel formation. We assessed total proteome chang ...[more]

PMID: 39096357

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Project description:Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here, we investigate the angiogenic functions of three separate nuclear genes that encode for mitochondrial proteins, including mitochondrial transcriptional factor (TFAM), respiratory complex IV component (COX10), and a mitochondrial redox protein thioredoxin 2 (TRX2), which are responsible for distinct mitochondrial functions. We aim to investigate if mitochondrial activities regulate common endothelial cell (EC) signaling pathways during angiogenesis. The silencing of Tfam, Cox10, or Trx2 in an in vitro 3D sprouting assay attenuates EC sprouting, which correlated with reduced EC proliferation but not with ROS generation or EC apoptosis. Mice with an inducible deletion of Tfam, Cox10, or Trx2 exhibit retarded retinal vessel growth without penetration into the deep plexi at early ages (P5-P12). The three mutant mice develop arteriovenous malformations (AVM) with microaneurysm formation in the microvessels at advanced ages (P12-P30); the hypovasculature and microaneurysm phenotypes resemble that of aged human retinas and human primitive retinal vascular abnormalities such as Coats’ disease, Leber’s military aneurysms and familial exudative vitreoretinopathy. Single-cell RNA-seq analyses of retinal ECs suggest that the three mutant mice have common EC clusters with reduced gene expressions in anion transporters, actin organization, extracellular matrix, and angiogenesis. These EC clusters also have increased gene expressions in endothelial-mesenchymal transition and arterial markers, correlating with enhanced TGFbR signaling in Tfam, Cox10, or Trx2-deficient mice. Importantly, pharmacological blockade by TGFbR inhibitors attenuated retinal vessel growth retardation and AVM formation in all three mutant mice. Our study demonstrates that mitochondrial dysfunction induces TGF-b receptor-mediated arteriovenous malformations and microaneurysm formation in mouse retinas, and provide a novel model and therapeutic intervention for human primitive retinal vascular abnormalities, which are characterized by retinal vascular malformations and are associated with many pathological complications such as diabetes and hypertension that can result in vision loss.