Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas

Haifeng Zhang, Busu Li, Qunhua Huang, Francesc López-Giráldez, Yoshiaki Tanaka, Qun Lin, Sameet Mehta, Guilin Wang, Morven Graham, Xinran Liu, In-Hyun Park, Anne Eichmann, Wang Min () and Jenny Huanjiao Zhou ()
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Haifeng Zhang: Yale University School of Medicine
Busu Li: Yale University School of Medicine
Qunhua Huang: Yale University School of Medicine
Francesc López-Giráldez: Yale University School of Medicine
Yoshiaki Tanaka: Yale University School of Medicine
Qun Lin: Yale University School of Medicine
Sameet Mehta: Yale University School of Medicine
Guilin Wang: Yale University School of Medicine
Morven Graham: Yale University School of Medicine
Xinran Liu: Yale University School of Medicine
In-Hyun Park: Yale University School of Medicine
Anne Eichmann: Yale University School of Medicine
Wang Min: Yale University School of Medicine
Jenny Huanjiao Zhou: Yale University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here we show that mice with endothelial deficiency of any one of the three nuclear genes encoding for mitochondrial proteins, transcriptional factor (TFAM), respiratory complex IV component (COX10), or redox protein thioredoxin 2 (TRX2), exhibit retarded retinal vessel growth and arteriovenous malformations (AVM). Single-cell RNA-seq analyses indicate that retinal ECs from the three mutant mice have increased TGFβ signaling and altered gene expressions associated with vascular maturation and extracellular matrix, correlating with vascular malformation and increased basement membrane thickening in microvesels of mutant retinas. Mechanistic studies suggest that mitochondrial dysfunction from Tfam, Cox10, or Trx2 depletion induces a mitochondrial localization and MAPKs-mediated phosphorylation of SMAD2, leading to enhanced ALK5-SMAD2 signaling. Importantly, pharmacological blockade of ALK5 signaling or genetic deficiency of SMAD2 prevented retinal vessel growth retardation and AVM in all three mutant mice. Our studies uncover a novel mechanism whereby mitochondrial dysfunction via the ALK5-SMAD2 signaling induces retinal vascular malformations, and have therapeutic values for the alleviation of angiogenesis-associated human retinal diseases.

Date: 2022
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DOI: 10.1038/s41467-022-35262-w

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