Gender Affects Skin Wound Healing in Plasminogen Deficient Mice

Abstract

The fibrinolytic activity of plasmin plays a fundamental role in resolution of blood clots and clearance of extravascular deposited fibrin in damaged tissues. These vital functions of plasmin are exploited by malignant cells to accelerate tumor growth and facilitate metastases. Mice lacking functional plasmin thus display decreased tumor growth in a variety of cancer models. Interestingly, this role of plasmin has, in regard to skin cancer, been shown to be restricted to male mice. It remains to be clarified whether gender also affects other phenotypic characteristics of plasmin deficiency or if this gender effect is restricted to skin cancer. To investigate this, we tested the effect of gender on plasmin dependent immune cell migration, accumulation of hepatic fibrin depositions, skin composition, and skin wound healing. Gender did not affect immune cell migration or hepatic fibrin accumulation in neither wildtype nor plasmin deficient mice, and the existing differences in skin composition between males and females were unaffected by plasmin deficiency. In contrast, gender had a marked effect on the ability of plasmin deficient mice to heal skin wounds, which was seen as an accelerated wound closure in female versus male plasmin deficient mice. Further studies showed that this gender effect could not be reversed by ovariectomy, suggesting that female sex-hormones did not mediate the accelerated skin wound healing in plasmin deficient female mice. Histological examination of healed wounds revealed larger amounts of fibrotic scars in the provisional matrix of plasmin deficient male mice compared to female mice. These fibrotic scars correlated to an obstruction of cell infiltration of the granulation tissue, which is a prerequisite for wound healing. In conclusion, the presented data show that the gender dependent effect of plasmin deficiency is tissue specific and may be secondary to already established differences between genders, such as skin thickness and composition.

Gender-Specific Differences in Surgical Site Infections: An Analysis of 438,050 Surgical Procedures from the German National Nosocomial Infections Surveillance System

“…Androgens were shown to have a proinflammatory effect on wounds, impairing re-epithelialization, whereas oestrogens had an anti-inflammatory effect, with males and females responding differently with regard to stress [ 13 ]. A study on plasminogen-deficient mice demonstrated marked gender effects on wound healing [ 14 ]. Loss of plasmin-dependent fibrinolysis leads to abnormal wound healing and development of pseudomembranes.…”

Recent Advances on Plasmin Inhibitors for the Treatment of Fibrinolysis‐Related Disorders

“…23 Plasmin is a serine protease that exhibits trypsin-like broad specificity, particularly when plasminogen is activated by urokinase plasminogen activator (uPA) in a cell surface receptormediated process. 24,25 Plasmin generated at the cell surface plays a critical role in degradation of extracellular matrix (ECM) resulting in modulation of several processes including tissue remodeling, 26,27 cell invasion and metastasis, 28,29 chemotaxis, 29,30 wound healing and tissue repair, [31][32][33] neuritogenesis, 34,35 ovulation and embryo implantation, 36,37 and others. 38 Plasmin itself can degrade components in the ECM such as laminin, 39 fibronectin, 40 and collagens.…”

Advantages in Wound Healing Process in Female Mice Require Upregulation A2A-Mediated Angiogenesis under the Stimulation of 17β-Estradiol

“…It is unclear whether this apparent advantage present in females also involves the wound healing process. In particular, the dorsal incisional wound healing process—generated in a similar experimental setting in this manuscript—showed no difference between C57BL/6 male and female mice after 50 days post-injury [ 2 ]. In this last report, female mice tended to have more rapid wound healing, especially in the time-lapse of up to 20 days.…”

“…A substantial body of evidence describes contrasting influences of androgenic and estrogenic sex steroids on the healing of acute skin wounds, in which the former inhibits whereas the latter accelerates recovery [ 1 ]. However, gender differences in wound repair parameters would not intuitively be expected [ 2 , 3 ]. Since healing is a complex mechanism involving several processes, such as inflammation, coagulation, and angiogenesis, among others, it is feasible that female mice may have certain advantages in some of those processes.…”