Negative pressure wound therapy promotes vessel destabilization and maturation at various stages of wound healing and thus influences wound prognosis

Zhanjun Ma, Kangquan Shou, Zonghuan Li, Chao Jian, Baiwen Qi, Aixi Yu, Zhanjun Ma, Kangquan Shou, Zonghuan Li, Chao Jian, Baiwen Qi, Aixi Yu

Abstract

Negative pressure wound therapy (NPWT) has been observed to accelerate the wound healing process in humans through promoting angiogenesis. However, the potential biological effect and relevant molecular mechanisms, including microvessel destabilization, regression and endothelial cell proliferation in the early stage (1-3 days), and the neovascular stabilization and maturation in the later stage (7-15 days), have yet to be fully elucidated. The current study aimed to research the potential effect of NPWT on angiogenesis and vessel maturation, and investigate relevant association between mature microvessels and wound prognosis, as well as the regulatory mechanisms in human wound healing. Patients in the present study (n=48) were treated with NPWT or a petrolatum gauze, and relevant growth factors and vessel changes were detected using various experimental methods. NPWT increased the expression levels of angiogenin-2 (Ang-2), and decreased the expression levels of Ang-1 and ratios of Ang-1/Ang-2 in the initial stages of wound healing. However, in the latter stages of wound healing, NPWT increased the expression levels of Ang-1 and ratios of Ang-1/Ang-2, as well as the phosphorylation level of tyrosine kinase receptor-2. Consequently, microvessel pericyte coverage was gradually elevated, and the basement membrane was gradually supplied with new blood at the later stage of wound healing. In conclusion, NPWT may preferentially stimulate microvessel destabilization and regression in the early stage of wound healing, and as a consequence, increase angiogenesis. Subsequently, in the later stage of wound healing, NPWT may preferentially promote microvessel stabilization, thereby promoting microvessel maturation in human wounds through the angiogenin/tyrosine kinase receptor-2 signaling pathway. The results of the present study results demonstrated that NPWT was able to accelerate wound healing speed, and thus influence wound prognosis, as a result of an abundance of mature microvessels in human wounds.

Keywords: negative pressure wound therapy; pericyte; vessel maturation; wound prognosis.

Figures

Figure 1.
Figure 1.
Microvessel blood flow perfusion changes and macroscopic wound healing in control and NPWT groups at different time points. (A) Microvessel blood flow perfusion was assessed on days 7 and 15 following surgery. (B) Statistical analysis of blood flow perfusion values in the two groups during wound healing. *P

Figure 2.

Immunofluorescence assay of proliferating endothelial…

Figure 2.

Immunofluorescence assay of proliferating endothelial cells in the wound in different groups. (A)…

Figure 2.
Immunofluorescence assay of proliferating endothelial cells in the wound in different groups. (A) Representative examples of double staining of Ki67 and CD31 (red, CD31; green, Ki67; nuclei, blue) in wound sections from the experimental and control groups on day 3 following surgery (magnification, x200). (B) Quantitative comparison of the PCI for the two groups. The PCI was used to evaluate the percentage of proliferating endothelial cells. Results are expressed as the mean ± standard deviation. *P

Figure 3.

Immunofluorescence analysis of MVD and…

Figure 3.

Immunofluorescence analysis of MVD and microvessel pericyte coverage in the two groups in…

Figure 3.
Immunofluorescence analysis of MVD and microvessel pericyte coverage in the two groups in the wound. (A) Samples from the groups were double stained to identify endothelial cells by CD31 (red) and pericyte by α-SMA expression (green) (magnification, x200). (B) The MVD was quantified at different time points. (C) Quantitative comparison of the numbers of microvessel pericyte in the different groups and at different time points. (D) The microvessel pericyte coverage index was quantified and analyzed in the two groups. All statistical analysis results are expressed as the mean ± standard deviation (*P

Figure 4.

Expression levels of Ang-1 and…

Figure 4.

Expression levels of Ang-1 and Ang-2 in the wound during the wound healing…

Figure 4.
Expression levels of Ang-1 and Ang-2 in the wound during the wound healing process. (A) Ang-1 gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in the two groups. (B) Statistical analysis for the protein expression levels of Ang-1 in the two groups. (C) Representative western blots showing the protein levels of Ang-1 in both groups. (D) RT-qPCR analysis gene levels of Ang-2 in the two groups. (E) Statistical analysis protein levels of Ang-2 in the two groups. (F) Representative western blots showing protein expression levels of Ang-2 in the two groups. (G) Protein expression ratio of Ang-1/Ang-2. All statistical analysis results are expressed as the mean ± standard deviation. *P

Figure 5.

Expression levels of pTie-2 and…

Figure 5.

Expression levels of pTie-2 and α-SMA in both groups during wound healing. (A)…

Figure 5.
Expression levels of pTie-2 and α-SMA in both groups during wound healing. (A) pTie-2 protein expression levels were quantified (*P
Similar articles
Cited by
References
    1. Zhang DM, Yang ZH, Zhuang PL, Wang YY, Chen WL, Zhang B. Role of negative-pressure wound therapy in the management of submandibular fistula after reconstruction for osteoradionecrosis. J Oral Maxillofac Surg. 2016;74:401–405. doi: 10.1016/j.joms.2015.09.012. - DOI - PubMed
    1. Ram M, Singh V, Kumawat S, Kumar D, Lingaraju MC, Singh Uttam T, Rahal A, Tandan Kumar S, Kumar D. Deferoxamine modulates cytokines and growth factors to accelerate cutaneous wound healing in diabetic rats. Eur J Pharmacol. 2015;764:9–21. doi: 10.1016/j.ejphar.2015.06.029. - DOI - PubMed
    1. Qin D, Trenkwalder T, Lee S, Chillo O, Deindl E, Kupatt C, Hinkel R. Early vessel destabilization mediated by Angiopoietin-2 and subsequent vessel maturation via Angiopoietin-1 induce functional neovasculature after ischemia. PLoS One. 2013;8:e61831. doi: 10.1371/journal.pone.0061831. - DOI - PMC - PubMed
    1. Hinkel R, Trenkwalder T, Kupatt C. Gene therapy for ischemic heart disease. Expert Opin Biol Ther. 2011;11:723–737. doi: 10.1517/14712598.2011.570749. - DOI - PubMed
    1. Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9:685–693. doi: 10.1038/nm0603-685. - DOI - PubMed
Show all 50 references
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Figure 2.
Figure 2.
Immunofluorescence assay of proliferating endothelial cells in the wound in different groups. (A) Representative examples of double staining of Ki67 and CD31 (red, CD31; green, Ki67; nuclei, blue) in wound sections from the experimental and control groups on day 3 following surgery (magnification, x200). (B) Quantitative comparison of the PCI for the two groups. The PCI was used to evaluate the percentage of proliferating endothelial cells. Results are expressed as the mean ± standard deviation. *P

Figure 3.

Immunofluorescence analysis of MVD and…

Figure 3.

Immunofluorescence analysis of MVD and microvessel pericyte coverage in the two groups in…

Figure 3.
Immunofluorescence analysis of MVD and microvessel pericyte coverage in the two groups in the wound. (A) Samples from the groups were double stained to identify endothelial cells by CD31 (red) and pericyte by α-SMA expression (green) (magnification, x200). (B) The MVD was quantified at different time points. (C) Quantitative comparison of the numbers of microvessel pericyte in the different groups and at different time points. (D) The microvessel pericyte coverage index was quantified and analyzed in the two groups. All statistical analysis results are expressed as the mean ± standard deviation (*P

Figure 4.

Expression levels of Ang-1 and…

Figure 4.

Expression levels of Ang-1 and Ang-2 in the wound during the wound healing…

Figure 4.
Expression levels of Ang-1 and Ang-2 in the wound during the wound healing process. (A) Ang-1 gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in the two groups. (B) Statistical analysis for the protein expression levels of Ang-1 in the two groups. (C) Representative western blots showing the protein levels of Ang-1 in both groups. (D) RT-qPCR analysis gene levels of Ang-2 in the two groups. (E) Statistical analysis protein levels of Ang-2 in the two groups. (F) Representative western blots showing protein expression levels of Ang-2 in the two groups. (G) Protein expression ratio of Ang-1/Ang-2. All statistical analysis results are expressed as the mean ± standard deviation. *P

Figure 5.

Expression levels of pTie-2 and…

Figure 5.

Expression levels of pTie-2 and α-SMA in both groups during wound healing. (A)…

Figure 5.
Expression levels of pTie-2 and α-SMA in both groups during wound healing. (A) pTie-2 protein expression levels were quantified (*P
Similar articles
Cited by
References
    1. Zhang DM, Yang ZH, Zhuang PL, Wang YY, Chen WL, Zhang B. Role of negative-pressure wound therapy in the management of submandibular fistula after reconstruction for osteoradionecrosis. J Oral Maxillofac Surg. 2016;74:401–405. doi: 10.1016/j.joms.2015.09.012. - DOI - PubMed
    1. Ram M, Singh V, Kumawat S, Kumar D, Lingaraju MC, Singh Uttam T, Rahal A, Tandan Kumar S, Kumar D. Deferoxamine modulates cytokines and growth factors to accelerate cutaneous wound healing in diabetic rats. Eur J Pharmacol. 2015;764:9–21. doi: 10.1016/j.ejphar.2015.06.029. - DOI - PubMed
    1. Qin D, Trenkwalder T, Lee S, Chillo O, Deindl E, Kupatt C, Hinkel R. Early vessel destabilization mediated by Angiopoietin-2 and subsequent vessel maturation via Angiopoietin-1 induce functional neovasculature after ischemia. PLoS One. 2013;8:e61831. doi: 10.1371/journal.pone.0061831. - DOI - PMC - PubMed
    1. Hinkel R, Trenkwalder T, Kupatt C. Gene therapy for ischemic heart disease. Expert Opin Biol Ther. 2011;11:723–737. doi: 10.1517/14712598.2011.570749. - DOI - PubMed
    1. Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9:685–693. doi: 10.1038/nm0603-685. - DOI - PubMed
Show all 50 references
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Figure 3.
Figure 3.
Immunofluorescence analysis of MVD and microvessel pericyte coverage in the two groups in the wound. (A) Samples from the groups were double stained to identify endothelial cells by CD31 (red) and pericyte by α-SMA expression (green) (magnification, x200). (B) The MVD was quantified at different time points. (C) Quantitative comparison of the numbers of microvessel pericyte in the different groups and at different time points. (D) The microvessel pericyte coverage index was quantified and analyzed in the two groups. All statistical analysis results are expressed as the mean ± standard deviation (*P

Figure 4.

Expression levels of Ang-1 and…

Figure 4.

Expression levels of Ang-1 and Ang-2 in the wound during the wound healing…

Figure 4.
Expression levels of Ang-1 and Ang-2 in the wound during the wound healing process. (A) Ang-1 gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in the two groups. (B) Statistical analysis for the protein expression levels of Ang-1 in the two groups. (C) Representative western blots showing the protein levels of Ang-1 in both groups. (D) RT-qPCR analysis gene levels of Ang-2 in the two groups. (E) Statistical analysis protein levels of Ang-2 in the two groups. (F) Representative western blots showing protein expression levels of Ang-2 in the two groups. (G) Protein expression ratio of Ang-1/Ang-2. All statistical analysis results are expressed as the mean ± standard deviation. *P

Figure 5.

Expression levels of pTie-2 and…

Figure 5.

Expression levels of pTie-2 and α-SMA in both groups during wound healing. (A)…

Figure 5.
Expression levels of pTie-2 and α-SMA in both groups during wound healing. (A) pTie-2 protein expression levels were quantified (*P
Similar articles
Cited by
References
    1. Zhang DM, Yang ZH, Zhuang PL, Wang YY, Chen WL, Zhang B. Role of negative-pressure wound therapy in the management of submandibular fistula after reconstruction for osteoradionecrosis. J Oral Maxillofac Surg. 2016;74:401–405. doi: 10.1016/j.joms.2015.09.012. - DOI - PubMed
    1. Ram M, Singh V, Kumawat S, Kumar D, Lingaraju MC, Singh Uttam T, Rahal A, Tandan Kumar S, Kumar D. Deferoxamine modulates cytokines and growth factors to accelerate cutaneous wound healing in diabetic rats. Eur J Pharmacol. 2015;764:9–21. doi: 10.1016/j.ejphar.2015.06.029. - DOI - PubMed
    1. Qin D, Trenkwalder T, Lee S, Chillo O, Deindl E, Kupatt C, Hinkel R. Early vessel destabilization mediated by Angiopoietin-2 and subsequent vessel maturation via Angiopoietin-1 induce functional neovasculature after ischemia. PLoS One. 2013;8:e61831. doi: 10.1371/journal.pone.0061831. - DOI - PMC - PubMed
    1. Hinkel R, Trenkwalder T, Kupatt C. Gene therapy for ischemic heart disease. Expert Opin Biol Ther. 2011;11:723–737. doi: 10.1517/14712598.2011.570749. - DOI - PubMed
    1. Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9:685–693. doi: 10.1038/nm0603-685. - DOI - PubMed
Show all 50 references
Related information
Full text links [x]
[x]
Cite
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Format: AMA APA MLA NLM

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The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

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Figure 4.
Figure 4.
Expression levels of Ang-1 and Ang-2 in the wound during the wound healing process. (A) Ang-1 gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in the two groups. (B) Statistical analysis for the protein expression levels of Ang-1 in the two groups. (C) Representative western blots showing the protein levels of Ang-1 in both groups. (D) RT-qPCR analysis gene levels of Ang-2 in the two groups. (E) Statistical analysis protein levels of Ang-2 in the two groups. (F) Representative western blots showing protein expression levels of Ang-2 in the two groups. (G) Protein expression ratio of Ang-1/Ang-2. All statistical analysis results are expressed as the mean ± standard deviation. *P

Figure 5.

Expression levels of pTie-2 and…

Figure 5.

Expression levels of pTie-2 and α-SMA in both groups during wound healing. (A)…

Figure 5.
Expression levels of pTie-2 and α-SMA in both groups during wound healing. (A) pTie-2 protein expression levels were quantified (*P
Similar articles
Cited by
References
    1. Zhang DM, Yang ZH, Zhuang PL, Wang YY, Chen WL, Zhang B. Role of negative-pressure wound therapy in the management of submandibular fistula after reconstruction for osteoradionecrosis. J Oral Maxillofac Surg. 2016;74:401–405. doi: 10.1016/j.joms.2015.09.012. - DOI - PubMed
    1. Ram M, Singh V, Kumawat S, Kumar D, Lingaraju MC, Singh Uttam T, Rahal A, Tandan Kumar S, Kumar D. Deferoxamine modulates cytokines and growth factors to accelerate cutaneous wound healing in diabetic rats. Eur J Pharmacol. 2015;764:9–21. doi: 10.1016/j.ejphar.2015.06.029. - DOI - PubMed
    1. Qin D, Trenkwalder T, Lee S, Chillo O, Deindl E, Kupatt C, Hinkel R. Early vessel destabilization mediated by Angiopoietin-2 and subsequent vessel maturation via Angiopoietin-1 induce functional neovasculature after ischemia. PLoS One. 2013;8:e61831. doi: 10.1371/journal.pone.0061831. - DOI - PMC - PubMed
    1. Hinkel R, Trenkwalder T, Kupatt C. Gene therapy for ischemic heart disease. Expert Opin Biol Ther. 2011;11:723–737. doi: 10.1517/14712598.2011.570749. - DOI - PubMed
    1. Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9:685–693. doi: 10.1038/nm0603-685. - DOI - PubMed
Show all 50 references
Related information
Full text links [x]
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 5.
Figure 5.
Expression levels of pTie-2 and α-SMA in both groups during wound healing. (A) pTie-2 protein expression levels were quantified (*P

References

    1. Zhang DM, Yang ZH, Zhuang PL, Wang YY, Chen WL, Zhang B. Role of negative-pressure wound therapy in the management of submandibular fistula after reconstruction for osteoradionecrosis. J Oral Maxillofac Surg. 2016;74:401–405. doi: 10.1016/j.joms.2015.09.012.
    1. Ram M, Singh V, Kumawat S, Kumar D, Lingaraju MC, Singh Uttam T, Rahal A, Tandan Kumar S, Kumar D. Deferoxamine modulates cytokines and growth factors to accelerate cutaneous wound healing in diabetic rats. Eur J Pharmacol. 2015;764:9–21. doi: 10.1016/j.ejphar.2015.06.029.
    1. Qin D, Trenkwalder T, Lee S, Chillo O, Deindl E, Kupatt C, Hinkel R. Early vessel destabilization mediated by Angiopoietin-2 and subsequent vessel maturation via Angiopoietin-1 induce functional neovasculature after ischemia. PLoS One. 2013;8:e61831. doi: 10.1371/journal.pone.0061831.
    1. Hinkel R, Trenkwalder T, Kupatt C. Gene therapy for ischemic heart disease. Expert Opin Biol Ther. 2011;11:723–737. doi: 10.1517/14712598.2011.570749.
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Source: PubMed

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