Elevated Circulation Levels of an Antiangiogenic SERPIN in Patients with Diabetic Microvascular Complications Impair Wound Healing through Suppression of Wnt Signaling

Jeffrey D. McBride, Alicia J. Jenkins, Xiaochen Liu, Bin Zhang, Kyungwon Lee, William L Berry, Ralf Janknecht, Courtney T. Griffin, Christopher E Aston, Timothy J. Lyons, James J Tomasek, Jian-Xing Ma

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

Wound healing, angiogenesis and hair follicle maintenance are often impaired in the skin of diabetic patients, but the pathogenesis has not been well understood. Here, we report that circulation levels of kallistatin, a member of the serine proteinase inhibitor (SERPIN) superfamily with anti-angiogenic activities, were elevated in Type 2 diabetic patients with diabetic vascular complications. To test the hypothesis that elevated kallistatin levels could contribute to a wound healing deficiency via inhibition of Wnt/β-catenin signaling, we generated kallistatin-transgenic (KS-TG) mice. KS-TG mice had reduced cutaneous hair follicle density, microvascular density, and panniculus adiposus layer thickness as well as altered skin microvascular hemodynamics and delayed cutaneous wound healing. Using Wnt reporter mice, our results showed that Wnt/β-catenin signaling is suppressed in dermal endothelium and hair follicles in KS-TG mice. Lithium, a known activator of β-catenin via inhibition of glycogen synthase kinase-3β, reversed the inhibition of Wnt/β-catenin signaling by kallistatin and rescued the wound healing deficiency in KS-TG mice. These observations suggest that elevated circulating anti-angiogenic serpins in diabetic patients may contribute to impaired wound healing through inhibition of Wnt/β-catenin signaling. Activation of Wnt/β-catenin signaling, at a level downstream of Wnt receptors, may ameliorate the wound healing deficiency in diabetic patients.Journal of Investigative Dermatology accepted article preview online, 24 January 2014. doi:10.1038/jid.2014.40.
Original languageEnglish
Pages (from-to)1725-1734
Number of pages10
JournalJournal of investigative dermatology
Volume134
Issue number6
Early online date13 Mar 2014
DOIs
Publication statusPublished - Jun 2014

ASJC Scopus subject areas

  • Dermatology
  • Molecular Biology
  • Cell Biology
  • Biochemistry

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