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

Abstract

Abstract. The aim of the present study was to investigate the mechanisms for impaired skin wound healing in subjects with diabetes. Type 1 diabetes (T1DM) was induced in BALB/c mice using streptozotocin. One month after the establishment of the T1DM mouse model, a wound was formed on the back of the mice, and tissues from the wounds and the margins were collected on days 0, 3, 7 and 10. Protein levels of cluster of differentiation 31 (CD31) were detected using immunohistochemistry, and the mRNA levels of Akt, hypoxia-inducible factor-1α (Hif-1α), vascular endothelial growth factor (Vegf ), VEGF receptor 2 (Vegfr2), stromal cell-derived growth factor-1α (Sdf-1α) and CXC chemokine receptor 4 (Cxcr4) were determined using reverse transcription-quantitative polymerase chain reaction analysis. The corresponding protein levels were determined using western blotting. The skin wound healing rate in the T1DM mice was significantly lower than that in the control mice, and the protein level of CD31 in the wounded skin of the T1DM mice was significantly decreased. Furthermore, the overall mRNA levels of Akt, Vegf, Vegfr2, and Cxcr4 in the T1DM mice were significantly lower than those in the control mice, and similar trends were observed in the protein levels. In conclusion, skin wound healing was impaired in the T1DM mice, and this may have been caused by a deficiency of Akt/HIF-1α and downstream signaling, as well as delayed angiogenesis. IntroductionDiabetes mellitus is a chronic disease threatening the health of individuals worldwide (1). There are multiple, often serious, complications associated with diabetes mellitus, one of which is impaired healing, which can lead to a reduction in physical activity and, in certain cases, chronic wounds and limb amputation (1,2). An imbalance between the pro-and anti-inflammatory mediators accentuates diabetic vascular complications and impedes proper wound healing (3). Other factors that contribute to deficient healing in patients with diabetes include altered host responses; attenuated antibacterial defenses; prolonged inflammation; changes in protease activity; insufficient cell production for rapid and robust healing; angiogenic disorders; decreased production of growth factors; inadequate extracellular matrix production; and changes in apoptosis (1-5).Wound healing is a complex process involving inflammation, granulation tissue formation, the production of new structures and tissue remodeling (2). The process is dependent upon a series of interactions between a variety of cell types, cytokine mediators and the extracellular matrix (1). In order for wound healing to be successful, a sufficient number of cells must be generated to participate in the repair (2,6,7). Processes that have a negative effect on the generation of an adequate cell number, such as inappropriately high levels of fibroblast apoptosis, may limit healing (6,7).Hypoxia-inducible factor (HIF)-1 is a master regulator of oxygen homeostasis and is comprised of HIF-1α, a finely regulated subunit, and HIF-1β (also ...

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

“…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.…”

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

“…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 ).…”

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

“…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.…”

“…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).…”

“…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).…”