Akt/hypoxia-inducible factor-1α signaling deficiency compromises skin wound healing in a type 1 diabetes mouse model

Jing, Lifeng; Li, Shuang; Li, Qin

doi:10.3892/etm.2015.2394

Cited by 16 publications

(9 citation statements)

References 25 publications

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“…For patho-physiological conditions with impaired wound healing and decreased HIF-1a expression, such as diabetic wounds, 28,29 as well as for conditions with enhanced vascularization, such as tumors expressing high levels of HIF-1a, 13 controlling SHP-2 activity may improve disease. Indeed, this was demonstrated by our in vivo technique using magnetic targeting of MNP-LV complexes to individual wounds of the mouse dorsal skinfold chamber.…”

Section: Discussionmentioning

confidence: 99%

HIF-1α Dependent Wound Healing Angiogenesis In Vivo Can Be Controlled by Site-Specific Lentiviral Magnetic Targeting of SHP-2

Heun

Pogoda²,

Anton

et al. 2017

Molecular Therapy

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Hypoxia promotes vascularization by stabilization and activation of the hypoxia inducible factor 1α (HIF-1α), which constitutes a target for angiogenic gene therapy. However, gene therapy is hampered by low gene delivery efficiency and non-specific side effects. Here, we developed a gene transfer technique based on magnetic targeting of magnetic nanoparticle-lentivirus (MNP-LV) complexes allowing site-directed gene delivery to individual wounds in the dorsal skin of mice. Using this technique, we were able to control HIF-1α dependent wound healing angiogenesis in vivo via site-specific modulation of the tyrosine phosphatase activity of SHP-2. We thus uncover a novel physiological role of SHP-2 in protecting HIF-1α from proteasomal degradation via a Src kinase dependent mechanism, resulting in HIF-1α DNA-binding and transcriptional activity in vitro and in vivo. Excitingly, using targeting of MNP-LV complexes, we achieved simultaneous expression of constitutively active as well as inactive SHP-2 mutant proteins in separate wounds in vivo and hereby specifically and locally controlled HIF-1α activity as well as the angiogenic wound healing response in vivo. Therefore, magnetically targeted lentiviral induced modulation of SHP-2 activity may be an attractive approach for controlling patho-physiological conditions relying on hypoxic vessel growth at specific sites.

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Section: Discussionmentioning

confidence: 99%

HIF-1α Dependent Wound Healing Angiogenesis In Vivo Can Be Controlled by Site-Specific Lentiviral Magnetic Targeting of SHP-2

Heun

Pogoda²,

Anton

et al. 2017

Molecular Therapy

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“…Akt1 is essential for the vascular dynamics in wound healing (Somanath et al 2008 ), and is activated by growth factors and cytokines, and downstream effectors include glucose, lipid metabolism-regulating molecules, and biological processes such as the inflammatory response, cell migration, proliferation, and apoptosis (Huang et al 2018 ). Akt1 is also activated by hypoxia-inducible factors which are required for proper tissue reaction in hypoxia-induced PrU also (Jing et al 2015 ). The AKT-pathway is also involved in both NGF and VEGF signaling (Huang et al 2015 ; Jere et al 2019 ), and TrkA decline in db/db mice may drive AKT-pathway impairment (Vines et al 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of skin wound healing in non-diabetic and diabetic mice in excision and pressure experimental wounds

et al. 2022

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Experimental models for chronic skin lesions are excision and pressure ulcer, defined as “open” and “closed” lesions, respectively, only the latter characterized by tissue hypoxia. Moreover, systemic diseases, such as diabetes mellitus, affect wound repair. Thus, models for testing new therapies should be carefully selected according to the expected targets. In this study, we present an extensive and comparative histological, immunohistochemical, and molecular characterization of these two lesions in diabetic (db/db) and non-diabetic (C57BL/6 J) mice. In db/db mice, we found significant reduction in PGP9.5-IR innervation, reduction of capillary network, and reduced expression of NGF receptors. We found an increase in VEGF receptor Kdr expression, and the PI3K-Akt signaling pathway at the core of the altered molecular network. Db/db mice with pressure ulcers showed an impairment in the molecular regulation of hypoxia-related genes (Hif1a, Flt1, and Kdr), while extracellular matrix encoding genes (Itgb3, Timp1, Fn1, Col4a1) were upregulated by hyperglycemia and lesions. Overall, the molecular analysis suggests that db/db mice have a longer inflammatory phase of the wound repair process, delaying the progression toward the proliferation and remodeling phases.

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“…Topical or oral administration of bFGF and VEGF has been investigated as a therapy for improving the healing of diabetic ulcers and wounds (Galiano et al, 2004; Matsumoto et al, 2013; Das et al, 2016). Furthermore, TGF-β inhibitors have been shown to work synergistically with VEGF to improve capillary growth in mouse wounds (Ferrari et al, 2009; Liu et al, 2009; Jing et al, 2015). In addition to proteins, molecular species, such as oxygen, affect the angiogenic activity in wounds.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to proteins, molecular species, such as oxygen, affect the angiogenic activity in wounds. Acute hypoxia present during the initial stages of wound healing induces the release of hypoxia inducible factor-1 (HIF-1), which promotes angiogenesis by stimulating the production of VEGF by inflammatory cells and ECs (Jing et al, 2015). In contrast, current therapies for non-healing wounds involve providing exogenous oxygen to wounds (i.e., inducing hyperoxia) (Hopf et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Our computational model has a number of limitations, owing to the assumptions made during model development, which were necessary to capture the complex nature of angiogenesis. First, we did not explicitly model hypoxia-induced HIF-1 signaling, which is known to initiate angiogenesis (Jing et al, 2015). However, we captured the role of hypoxia in angiogenesis regulation by using a feedback function [ f V EGF ( O ) in Supplementary Table S2] that changes the rate of VEGF production based on the oxygen levels in the wound (van Vlimmeren et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Predictive Approach Identifies Molecular Targets and Interventions to Restore Angiogenesis in Wounds With Delayed Healing

et al. 2019

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Impaired angiogenesis is a hallmark of wounds with delayed healing, and currently used therapies to restore angiogenesis have limited efficacy. Here, we employ a computational simulation-based approach to identify influential molecular and cellular processes, as well as protein targets, whose modulation may stimulate angiogenesis in wounds. We developed a mathematical model that captures the time courses for platelets, 9 cell types, 29 proteins, and oxygen, which are involved in inflammation, proliferation, and angiogenesis during wound healing. We validated our model using previously published experimental data. By performing global sensitivity analysis on thousands of simulated wound-healing scenarios, we identified six processes (among the 133 modeled in total) whose modulation may improve angiogenesis in wounds. By simulating knockouts of 25 modeled proteins and by simulating different wound-oxygenation levels, we identified four proteins [namely, transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and angiopoietin-2 (ANG-2)], as well as oxygen, as therapeutic targets for stimulating angiogenesis in wounds. Our modeling results indicated that simultaneous inhibition of TGF-β and supplementation of either FGF-2 or ANG-2 could be more effective in stimulating wound angiogenesis than the modulation of either protein alone. Our findings suggest experimentally testable intervention strategies to restore angiogenesis in wounds with delayed healing.

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Akt/hypoxia-inducible factor-1α signaling deficiency compromises skin wound healing in a type 1 diabetes mouse model

Cited by 16 publications

References 25 publications

HIF-1α Dependent Wound Healing Angiogenesis In Vivo Can Be Controlled by Site-Specific Lentiviral Magnetic Targeting of SHP-2

HIF-1α Dependent Wound Healing Angiogenesis In Vivo Can Be Controlled by Site-Specific Lentiviral Magnetic Targeting of SHP-2

Molecular mechanisms of skin wound healing in non-diabetic and diabetic mice in excision and pressure experimental wounds

Predictive Approach Identifies Molecular Targets and Interventions to Restore Angiogenesis in Wounds With Delayed Healing

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