Endothelial Dysfunction May Play a Key Role in Keloid and Hypertrophic Scar Pathogenesis - Keloids and Hypertrophic Scars May Be Vascular Disorders

Med Hypotheses. 2016 Nov;96:51-60. doi: 10.1016/j.mehy.2016.09.024. Epub 2016 Sep 28.

Abstract

Keloids and hypertrophic scars are fibroproliferative disorders (FPDs) of the skin that result from abnormal healing of injured or irritated skin. They can be called pathological or inflammatory scars. Common causes are trauma, burn, surgery, vaccination, skin piercing, folliculitis, acne, and herpes zoster infection. The pathogenesis of these scars clearly involves local conditions such as delayed wound healing, wound depth, and the tension of the skin around the scars. Scar severity is also shaped by interactions between these local factors and genetic and systemic factors such as hypertension and sex hormones. Notably, to evaluate scar severity, the Japan Scar Workshop (JSW) has established the JSW Scar Scale. Our studies show that tension on the skin around the wound results in prolonged and/or repeated bouts of inflammation in the reticular layer of the dermis and that this inflammation generates abnormal numbers of blood vessels (as well as collagen and nerve fibers) in the dermal reticular layer. We hypothesize that local factors, such as the mechanobiology of the dermis and blood vessels, along with genetic and systemic factors promote pathological scar development by inducing endothelial dysfunction (i.e., vascular hyperpermeability) during the inflammatory stage of wound healing. The continued presence of these factors prolongs the influx of inflammatory cells and factors, thereby leading to fibroblast dysfunction. Evidence for this hypothesis includes the fact that all effective treatments of keloids, namely, radiotherapy, compression therapy, steroid administration, and long-pulsed Nd:YAG laser therapy, act, at least partly, by suppressing blood vessels. At present, keloids are classified as strongly inflammatory scars, while hypertrophic scars are considered to be mildly inflammatory scars. However, we propose that keloids and hypertrophic scars are simply manifestations of the same skin FPD and differ only in the degree of endothelial dysfunction and therefore inflammation. We therefore suggest that these pathological scars should be classified on the basis of the factor that causes the endothelial dysfunction. Thus, primary scars are caused by congenital endothelial dysfunction (e.g., a mutation prevents endothelial gaps from closing smoothly) while secondary scars are caused by endothelial dysfunction that results from aging, arterial sclerosis, and/or repeated/very strong local mechanical forces. We expect that primary keloids develop at younger ages and tend to become severe, while secondary keloids are seen in all ages and can vary in clinical severity. Thus, abnormal blood vessel regulation may underlie keloid and hypertrophic scar pathogenesis, which suggests that inhibiting abnormal angiogenesis and vascular hyperpermeability may be an important therapeutic approach.

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use
  • Burns / complications
  • Cell Movement
  • Cicatrix, Hypertrophic / pathology*
  • Disease Progression
  • Endothelium / physiopathology*
  • Female
  • Fibroblasts / pathology
  • Humans
  • Inflammation
  • Keloid / etiology*
  • Lasers
  • Male
  • Radiotherapy / methods
  • Skin / pathology*
  • Wound Healing

Substances

  • Adrenal Cortex Hormones