title: Skin Wound Repair Is Not Altered in the Absence of Endogenous AnxA1 or AnxA5, but Pharmacological Concentrations of AnxA4 and AnxA5 Inhibit Wound Hemostasis.
abstract: Skin injury induces the cell surface exposure of phosphatidylserine (PS) on damaged and dying cells to activate coagulation and repair processes. Annexins can bind to PS and may modulate the healing response. Here, we determine the relevance of annexins for skin wound healing using AnxA1- and AnxA5-deficient mice and recombinant annexins with distinct PS binding properties. Wound inflammation, closure and the formation of granulation tissue were not altered in AnxA1- or AnxA5-deficient mice or after increasing AnxA5 serum concentrations (100 nM) in wild-type mice. Increased serum concentrations (1 µM) of AnxA5 induced massive bleeding, but wound hemostasis was not delayed by AnxA1. Both annexins interact with PS, but only AnxA5 can form 2-dimensional (2D) arrays on the cell surface. The injection of an AnxA5 mutant that binds to PS but lacks the ability of 2D array formation failed to induce bleeding. 2D lattice-forming AnxA4, with high affinity to PS also caused bleeding, while hemostasis was not affected by AnxA8 with low affinity or the AnxA8 mutant with medium affinity for PS and the lack of 2D formation. Increased concentrations of AnxA4 and AnxA5 also delayed coagulation pathway activation in vitro. This effect was attenuated for the AnxA5 mutant as well as for AnxA1 and AnxA8. In conclusion, endogenous AnxA1 and AnxA5 are dispensable for wound hemostasis and repair, but pharmacologically excessive concentrations of AnxA4 and AnxA5 inhibit hemostasis in skin wounds.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kreft
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Klatt
authors.forename: Julia
authors.initials: J
authors.lastname: Straßburger
authors.forename: Ernst
authors.initials: E
authors.lastname: Pöschl
authors.forename: Rod J
authors.initials: RJ
authors.lastname: Flower
authors.forename: Sabine
authors.initials: S
authors.lastname: Eming
authors.forename: Chris
authors.initials: C
authors.lastname: Reutelingsperger
authors.forename: Alain
authors.initials: A
authors.lastname: Brisson
authors.forename: Bent
authors.initials: B
authors.lastname: Brachvogel
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000172:deficiency* / Q000235:genetics; D017314:Annexin A4 / Q000494:pharmacology*; D017304:Annexin A5 / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D005434:Flow Cytometry; D006470:Hemorrhage / Q000188:drug therapy*; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010718:Phosphatidylserines / Q000378:metabolism; D011517:Prothrombin Time; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin / Q000293:injuries; D014945:Wound Healing / Q000502:physiology*
chemical_list: D017305:Annexin A1; D017314:Annexin A4; D017304:Annexin A5; D010718:Phosphatidylserines; D011994:Recombinant Proteins; C573274:annexin A1, mouse