Investigating the Role of PPARβ/δ in Retinal Vascular Remodeling Using Pparβ/δ-Deficient Mice

Ho, Sze Yuan; Kwan, Yuet Ping; Qiu, Beiying; Tan, Alison; Murray, Hannah; Barathi, Veluchamy A; Tan, Nguan Soon; Cheung, Chui Ming Gemmy; Wong, Tien Yin; Wahli, Walter; Wang, Xiaomeng

doi:10.3390/ijms21124403

Cited by 6 publications

(2 citation statements)

References 66 publications

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“…However, the influence of in vivo loss of PPARδ on angiogenesis or other functions of EC, in addition to vascular tone, remains unclear. The involvement of endogenous PPARδ has only been shown recently using global Ppard knockout mice which suggested a reduced retinal angiogenesis and vessel remodeling only at steady state 38 . In the present study, we found that ischemia-induced angiogenesis and possibly vasculogenesis was impaired in the Ppard EC-KO mice, suggested by a delayed appearance of capillary ECs and arterioles, accompanied by the failure to upregulate many angiogenic factors including the VEGF signaling.…”

Section: Discussionmentioning

confidence: 99%

Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α

Wu¹,

Tang²,

Lee³

et al. 2022

Theranostics

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Rationale: Restoration of vascular perfusion in peripheral arterial disease involves a combination of neovessel formation and the functional restoration of vascular endothelium. Previous studies indicated that ligand-dependent PPARδ activation enhances angiogenesis. However, how PPARδ is triggered by hypoxia and its downstream effects during post-ischemic vascular repair was not well understood. Methods: We induced experimental hindlimb ischemia in endothelial cell selective Ppard knockout induced by Cdh5-Cre mediated deletion of floxed Ppard allele in mice and their wild type control and observed blood perfusion, capillary density, vascular relaxation, and vascular leakage. Results: Deletion of endothelial Ppard delayed perfusion recovery and tissue repair, accompanied by delayed post-ischemic angiogenesis, impaired restoration of vascular integrity, more vascular leakage and enhanced inflammatory responses. At the molecular level, hypoxia upregulated and activated PPARδ in endothelial cells, whereas PPARδ reciprocally stabilized HIF1α protein to prevent its ubiquitin-mediated degradation. PPARδ directly bound to the oxygen-dependent degradation domain of HIF1α at the ligand-dependent domain of PPARδ. Importantly, this HIF1α-PPARδ interaction was independent of PPARδ ligand. Adeno-associated virus mediated endothelium-targeted overexpression of stable HIF1α in vivo improved perfusion recovery, suppressed vascular inflammation, and enhanced vascular repair, to counteract with the effect of Ppard knockout after hindlimb ischemia in mice. Conclusions: In summary, hypoxia-induced, ligand-independent activation of PPARδ in ECs stabilizes HIF1α and serves as a critical regulator for HIF1α activation to facilitate the post-ischemic restoration of vascular homeostasis.

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Section: Discussionmentioning

confidence: 99%

Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α

Wu¹,

Tang²,

Lee³

et al. 2022

Theranostics

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“…In ophthalmology, PPARs have recently been reported to affect inflammation, fibrosis, and angiogenesis [13,14,18,19]. However, there are few reports of the effects of PPARs on corneal epithelial wound healing.…”

Section: Discussionmentioning

confidence: 99%

Effects of Selective Peroxisome Proliferator Activated Receptor Agonists on Corneal Epithelial Wound Healing

et al. 2021

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The effects of each subtype-selective peroxisome proliferator activated receptor (PPAR) agonist (α, β/δ, γ) on corneal epithelial wound healing were investigated using a rat corneal alkali burn model. After the alkali burn, each PPAR agonist or vehicle ophthalmic solution was instilled topically onto the rat’s cornea. Corneal epithelial healing processes were evaluated by fluorescein staining. Pathological analyses and real-time reverse transcription polymerase chain reactions were performed to evaluate Ki67 (proliferative maker) expression and inflammatory findings. The area of the corneal epithelial defect at 12 h and 24 h after the alkali burn was significantly smaller in each PPAR group than in the vehicle group. Ki67 mRNA expression was increased in the PPARβ/δ group, whereas mRNA expressions of inflammatory cytokines were suppressed in all of the PPAR agonist groups. Nuclear factor kappa B (NF-κB) was the most suppressed in the PPARγ group. The accelerated corneal epithelial healing effects of each PPAR ligand were thought to be related to the promotion of proliferative capacity and inhibition of inflammation.

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Perfluorooctane sulfonate and perfluorooctanoic acid

Kuzukiran

Simsek

Filazı

et al. 2022

Reproductive and Developmental Toxicology

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Investigating the Role of PPARβ/δ in Retinal Vascular Remodeling Using Pparβ/δ-Deficient Mice

Cited by 6 publications

References 66 publications

Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α

Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α

Effects of Selective Peroxisome Proliferator Activated Receptor Agonists on Corneal Epithelial Wound Healing

Perfluorooctane sulfonate and perfluorooctanoic acid

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