α2AP regulates vascular alteration by inhibiting VEGF signaling in systemic sclerosis: the roles of α2AP in vascular dysfunction in systemic sclerosis

Kanno, Yosuke; Shu, En; Kanoh, Hiroyuki; Matsuda, Ayaka; Seishima, Mariko

doi:10.1186/s13075-017-1227-y

Cited by 15 publications

(28 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…VEGF exists in endothelial cells and various non‐endothelial cells . Without doubt, VEGF is mainly expressed in endothelial cells including umbilical vein endothelial cell, retinal pigmentary epithelial cells, bronchial, alveolar epithelial cells and so on . Moreover, the tube formation of HUVECs was commonly performed to evaluate the angiogenesis activity in skin wound healing .…”

Section: Discussionsupporting

confidence: 66%

See 1 more Smart Citation

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

Hua

et al. 2019

Experimental Dermatology

View full text Add to dashboard Cite

Hydrogen sulphide (H2S) is an important gasotransmitter with several physiological functions. However, the roles and the detailed mechanisms of H2S on skin wound healing are not known well. In the present study, 129S1/SvImJ mice were intraperitoneally injected with NaHS (50 μmol/kg/d) for 2 weeks. Then, a round wound of 6 mm diameter with depth into the dermis was made. The skin wound area, blood perfusion, superoxide production, malondialdehyde (MDA) levels, total antioxidant capacity (T‐AOC), expression of vascular endothelial growth factor (VEGF), dynamin‐related protein 1 (DRP1) and optic atrophy 1 (OPA1) were measured. After NaHS (50 μmol/L) pre‐administration for 4 hours, cell migration rate, DRP1, OPA1 and α–smooth muscle actin (α‐SMA) expression, superoxide production and mitochondrial membrane potential in primary skin fibroblasts were measured. Tube formation in human umbilical vein endothelial cells (HUVECs) and cell migration in human keratinocytes were also measured. The results showed that NaHS pretreatment significantly accelerated wound healing and improved blood flow in the wound after operation. NaHS increased VEGF expression in the wound and promoted tube formation in HUVECs. Meanwhile, NaHS attenuated reactive oxygen species (ROS) production, suppressed MDA level but restored T‐AOC in the wound. NaHS also promoted skin fibroblasts migration and α‐SMA expression after scratch. Moreover, NaHS alleviated ROS, increased mitochondrial membrane potential, decreased DRP1 but enhanced OPA1 expression in skin fibroblasts after scratch. NaHS also accelerated human keratinocytes migration after scratch. Taken together, exogenous H2S supplementary accelerated the skin wound healing, which might be related to oxidative stress inhibition and VEGF enhancement.

show abstract

Section: Discussionsupporting

confidence: 66%

“…As well as we know, VEGF is mainly expressed in endothelial cells . Next, the effect of NaHS on tube formation of HUVECs was investigated to evaluate the activity of blood formation in vitro.…”

Section: Resultssupporting

confidence: 47%

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

Hua

et al. 2019

Experimental Dermatology

View full text Add to dashboard Cite

show abstract

“…uPAR is involved in the high-molecular-weight kininogen (HKa)-mediated apoptoic effect [110]. α2AP induces vascular damage, such as the reduction of blood vessels and blood flow in mice, and α2AP neutralization improves vascular damage in SSc model mice [33]. In addition, α2AP is associated with vascular remodeling and EC apoptosis [57].…”

Section: The Role Of Fibrinolytic Regulators In Vascular and Ec Inmentioning

confidence: 99%

“…Furthermore, uPAR-deficient mice develop vasculopathy [8]. α2AP induces vascular injury, and α2AP deficiency attenuates the SSc-associated vascular dysfunction in SSc model mice [33]. These fibrinolytic regulators may be associated with the SSc-associated vascular disorders.…”

Section: Introductionmentioning

confidence: 99%

The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis

Kanno

2019

IJMS

Self Cite

View full text Add to dashboard Cite

Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by vascular dysfunction and extensive fibrosis of the skin and visceral organs. Vascular dysfunction is caused by endothelial cell (EC) apoptosis, defective angiogenesis, defective vasculogenesis, endothelial-to-mesenchymal transition (EndoMT), and coagulation abnormalities, and exacerbates the disease. Fibrinolytic regulators, such as plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1), and angiostatin, are considered to play an important role in the maintenance of endothelial homeostasis, and are associated with the endothelial dysfunction of SSc. This review considers the roles of fibrinolytic factors in vascular dysfunction of SSc.

show abstract

“…Alpha2-antiplasmin (α2AP) is known to be the principal inhibitor of plasmin, resulting in the formation of a stable inactive complex, plasmin-α2AP (PAP), and inhibits fibrinolysis and ECM degradation [6][7][8]. α2AP is synthesized in various tissues; has various functions, such as cytokine production, cell growth, and cell differentiation; and regulates angiogenesis, inflammatory response, immune modulation, tissue repair, bone formation, and brain functions [9][10][11][12][13][14][15][16][17][18]. Many studies have reported that the levels of PAP in plasma are elevated in fibrotic diseases which include systemic sclerosis (SSc), diabetic nephropathy, liver cirrhosis, and rheumatoid arthritis [19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Alternatively activated macrophages are associated with the α2AP production that occurs with the development of dermal fibrosis

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background: Fibrotic diseases are characterized by tissue overgrowth, hardening, and/or scarring because of the excessive production, deposition, and contraction of the extracellular matrix (ECM). However, the detailed mechanisms underlying these disorders remain unclear. It was recently reported that α2-antiplasmin (α2AP) is elevated in fibrotic tissue and that it is associated with the development of fibrosis. In the present study, we examined the mechanism underlying the production of α2AP on the development of fibrosis. Methods: To clarify the mechanism underlying the production of α2AP on the development of fibrosis, we focused on high-mobility group box 1 (HMGB1), which is associated with the development of fibrosis. The mouse model of bleomycin-induced fibrosis was used to evaluate the production of α2AP on the development of fibrosis. Results: We found that HMGB1 induced the production of α2AP through receptor for advanced glycation end products (RAGE) in fibroblasts. Next, we showed that macrophage reduction by a macrophage-depleting agent, clodronate, attenuated the progression of fibrosis and the production of α2AP and HMGB1 in the bleomycininduced mice. We also showed that IL-4-stimulated alternatively activated macrophages induced the production of HMGB1, that IL-4-stimulated alternatively activated macrophage conditioned media (CM) induced pro-fibrotic changes and α2AP production, and that the inhibition of HMGB1 and RAGE attenuated these effects in fibroblasts. Furthermore, the blockade of IL-4 signaling by IL-4Rα neutralizing antibodies attenuated the progression of fibrosis and the production of α2AP and HMGB1 in the bleomycin-induced mice.(Continued on next page) Conclusion: These findings suggest that alternatively activated macrophage-derived HMGB1 induced the production of α2AP through RAGE and that these effects are associated with the development of fibrosis. Our findings may provide a clinical strategy for managing fibrotic disorders.

show abstract

α2AP regulates vascular alteration by inhibiting VEGF signaling in systemic sclerosis: the roles of α2AP in vascular dysfunction in systemic sclerosis

Cited by 15 publications

References 21 publications

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis

Alternatively activated macrophages are associated with the α2AP production that occurs with the development of dermal fibrosis

Contact Info

Product

Resources

About