title: Pigment epithelium-derived factor as a multifunctional regulator of wound healing.
abstract: During dermal wound repair, hypoxia-driven proliferation results in dense but highly permeable, disorganized microvascular networks, similar to those in solid tumors. Concurrently, activated dermal fibroblasts generate an angiopermissive, provisional extracellular matrix (ECM). Unlike cancers, wounds naturally resolve via blood vessel regression and ECM maturation, which are essential for reestablishing tissue homeostasis. Mechanisms guiding wound resolution are poorly understood; one candidate regulator is pigment epithelium-derived factor (PEDF), a secreted glycoprotein. PEDF is a potent antiangiogenic in models of pathological angiogenesis and a promising cancer and cardiovascular disease therapeutic, but little is known about its physiological function. To examine the roles of PEDF in physiological wound repair, we used a reproducible model of excisional skin wound healing in BALB/c mice. We show that PEDF is abundant in unwounded and healing skin, is produced primarily by dermal fibroblasts, binds to resident microvascular endothelial cells, and accumulates in dermal ECM and epidermis. PEDF transcript and protein levels were low during the inflammatory and proliferative phases of healing but increased in quantity and colocalization with microvasculature during wound resolution. Local antibody inhibition of endogenous PEDF delayed vessel regression and collagen maturation during the remodeling phase. Treatment of wounds with intradermal injections of exogenous, recombinant PEDF inhibited nascent angiogenesis by repressing endothelial proliferation, promoted vascular integrity and function, and increased collagen maturity. These results demonstrate that PEDF contributes to the resolution of healing wounds by causing regression of immature blood vessels and stimulating maturation of the vascular microenvironment, thus promoting a return to tissue homeostasis after injury.
authors.affiliation: Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Mateusz S
authors.initials: MS
authors.lastname: Wietecha
authors.affiliation: Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Mateusz J
authors.initials: MJ
authors.lastname: Król
authors.affiliation: Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Michalczyk
authors.affiliation: Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Gettins
authors.affiliation: Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois; and Ldipiet@uic.edu.
authors.forename: Luisa A
authors.initials: LA
authors.lastname: DiPietro
mesh_terms: D000818:Animals; D002460:Cell Line; D002921:Cicatrix; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D062326:Re-Epithelialization; D015843:Serpins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D003094:Collagen; D005136:Eye Proteins; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor
keywords: PEDF/SERPINF1; angiogenesis; extracellular matrix remodeling; vessel regression; wound healing