Elevated circulation levels of an antiangiogenic SERPIN in patients with diabetic microvascular complications impair wound healing through suppression of Wnt signaling.
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 antiangiogenic 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 the 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 the 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 antiangiogenic 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.
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Jeffrey D
JD
McBride
Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
Alicia J
AJ
Jenkins
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Xiaochen
X
Liu
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Bin
B
Zhang
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Kyungwon
K
Lee
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
William L
WL
Berry
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Ralf
R
Janknecht
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Courtney T
CT
Griffin
Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Christopher E
CE
Aston
Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Timothy J
TJ
Lyons
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
James J
JJ
Tomasek
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. Electronic address: jian-xing-ma@ouhsc.edu.
Jian-Xing
JX
Ma
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2; D003925:Diabetic Angiopathies / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018859:Hair Follicle / Q000378:metabolism; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D015843:Serpins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000098:blood supply / Q000378:metabolism; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway; D014945:Wound Healing
D015843:Serpins; C051324:kallistatin; D008094:Lithium; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3