Pigment epithelium-derived factor as a multifunctional regulator of wound healing

Abstract

Wietecha MS, Król MJ, Michalczyk ER, Chen L, Gettins PG, DiPietro LA. Pigment epithelium-derived factor as a multifunctional regulator of wound healing. Am J Physiol Heart Circ Physiol 309: H812-H826, 2015. First published July 10, 2015; doi:10.1152/ajpheart.00153.2015.-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.

Skin Wound Healing: An Update on the Current Knowledge and Concepts

“…Recent research demonstrated that skin wounds healed normally despite reduced angiogenesis [57,58]. This observation is further supported by the fact that wounds in fetal skin and the oral mucosa heal without scarring despite less angiogenesis compared with adult skin [57,59].…”

Non‐invasive longitudinal monitoring of angiogenesis in a murine full‐thickness cutaneous wound healing model using high‐resolution three‐dimensional ultrasound imaging

“…A CD31 antibody has frequently been used to stain endothelial cells. 11,21,24,25 In this study, the results of paired measurements obtained from 2D ultrasound images with the Color Doppler mode and immunohistologically stained sections on day 14 after wounding showed that Pearson's correlation coefficients were r=0.927, 0.871, 0.717, and 0.913 for wounds 1, 2, 3, and 4, respectively, indicating a correlation. This result showed that a strong correlation for % vascularity was obtained between paired 2D ultrasound imaging with the Color Doppler mode and sections immunohistologically stained for the anti-CD31 antibody.…”

A Role for Low-Density Lipoprotein Receptor-Related Protein 6 in Blood Vessel Regression in Wound Healing

“…Eight-week old-female C57BL/6 mice (Harlan Laboratories, Inc., Indianapolis, IN) were subjected to standardized skin wounds 12 as previously described. Briefly, mice were anesthetized with ketamine (100 mg/kg) and xylazine (5 mg/kg), and two 3-mm-diameter full-thickness excisional wounds were made on the shaved dorsal skin using a biopsy punch (Acuderm, Inc., Ft. Lauderdale, FL).…”

“…Topical recombinant PEDF (rPEDF) treatment was applied daily to each wound until day 10 postinjury as described in our previous study. 12 For the first 3 days, 2 lg of rPEDF in 10 lL 25% pluronic gel (Sigma-Aldrich, St. Louis, MO) was directly applied to the surface of each wound. From day 4 to 10, 2 lg rPEDF in 10 lL phosphate-buffered saline (PBS) was injected intradermally into each wound.…”

“…10,11 More recent studies in our laboratory demonstrate that pigment epitheliumderived factor (PEDF) is likely to be the most significant mediator of vessel regression in wounds, and that PEDF provides the necessary signals required to remove immature capillaries. 12 Several receptors for PEDF have been identified, yet the distribution and function of these receptors among the cell types found in dermal wounds is unclear. 13 In this study, we focus on lipoprotein receptor-related protein 6 (Lrp6) as a candidate PEDF receptor in wounds, primarily due to its well-described ability to modulate Wnt signaling in processes, such as fibrosis, tumorigenesis, and angiogenesis, in other systems.…”