Stimulated neovascularization, inflammation resolution and collagen maturation in healing rat cutaneous wounds by a heparan sulfate glycosaminoglycan mimetic, OTR4120.
Heparan sulfate glycosaminoglycans (HS-GAGs) are not only the structural elements of tissue architecture but also regulate the bioavailability and transduction pathways of heparan sulfate-bound polypeptides released by cells or the extracellular matrix. Heparan sulfate-bound polypeptides include inflammatory mediators, chemokines, angiogenic factors, morphogens, and growth-promoting factors that induce cell migration, proliferation, and differentiation in wound healing. OTR4120, a polymer engineered to mimic the properties of HS-GAGs, is used to replace the natural HS-GAGs that are degraded during wound repair, and enhance the tissue regeneration by preserving the cellular microenvironment and the endogenous signals needed for tissue regeneration. We previously demonstrated that OTR4120 treatment had a long-term effect on increasing breaking strength and vasodilation in healing rat full-thickness excisional wounds. The present study investigates the underlying mechanisms of the effects of OTR4120 treatment in improving the quality of cutaneous wound repair. We found that OTR4120 treatment stimulated inflammation resolution and increased neovascularization. OTR4120 treatment also promoted epidermal migration and proliferation during reepithelialization. Moreover, the granulation tissue formation and collagen maturation were improved in OTR4120-treated wounds. Three months after wounding, the effects of OTR4120 treatment on vascularization and inflammation resolution were normalized, except for an improved neodermis. We conclude that OTR4120 is a potential matrix therapeutic agent that ensures the quality of normal cutaneous wound repair and may restore impaired wound healing characterized by deficient angiogenesis and prolonged inflammation.
Tong
Miao
M
Department of Plastic and Reconstructive Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Tuk
Bastiaan
B
Hekking
Ineke M
IM
Vermeij
Marcel
M
Barritault
Denis
D
van Neck
Johan W
JW
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003094:Collagen / Q000187:drug effects*; D004195:Disease Models, Animal; D006025:Glycosaminoglycans / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D012883:Skin Ulcer / Q000188:drug therapy* / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
D000893:Anti-Inflammatory Agents; D006025:Glycosaminoglycans; C533322:OTR4120; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D003094:Collagen