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Yang et al. Plast Aesthet Res 2020;7:34 I http://dx.doi.org/10.20517/2347-9264.2020.24 Page 5 of 10

Stress hormones could activate α-ARs to promote keloid formation by enhancing growth-
related responses and aggravating local hypoxia environment
The α-ARs are another group of adrenergic receptors that were found to be increased in keloid tissues
and peripheral sensory neurons of scarred skin. Stress hormones could activate α-ARs to promote keloid
formation by enhancing growth-related responses and aggravating the local hypoxia environment.
Furthermore, their enhanced expression was associated with cell proliferation, inflammation, and
uncomfortable symptoms of pain and pruritus in hypertrophic scars.

Activated α-ARs can evoke growth-related responses after bonding to stress hormones (NE, E). For
example, the α-1B subtype stimulates cell proliferation [27-29] and the activation of the α-1A subtype
[30]
evokes protein biosynthesis and cell hypertrophy . Tissue biopsy and immunohistochemistry detected
an increase of α-ARs in keloid scars compared to burn scars and unscarred skins in the regenerated
epidermis, dense bands of cells in the upper dermis and collagen fibers in the deep dermis, coinciding
[31]
with the inflammatory and proliferative stage . Since it was reported that injury-induced growth-related
responses are α1-AR subtype-dependent [32-34] , over-expression of α1-ARs might result in both hyperplasia
and hypertrophy of fibroblasts and vascular smooth muscles in keloid tissues. Moreover, the adrenergic
activation of fibroblasts could increase the production of extracellular matrix proteins (such as collagen
and fibronectin) and the expression of α1-ARs in peripheral sensory neurons was in line with enhanced
sensitivity to adrenergic agents in injured tissues, suggesting that the up-regulation of α1-ARs might not
only be involved in the inflammation and wound healing processes, but also be a significant source of pain,
[31]
itching, and hyperaesthesia .

Apart from α1-AR-induced growth-related responses that have been discussed, the vasoconstriction caused
by activated α1-ARs in vascular smooth muscles is another important aspect that could aggravate the local
hypoxia of keloid microenvironment and trigger hypoxia-related pathogenesis. Hypoxia is a common
environmental stress factor associated with various physiological and pathological conditions, including
angiogenesis, cell proliferation, glucose metabolism, pH regulation, and migration [35,36] . Accumulating
evidence suggested an anoxic microenvironment is crucial in keloid pathogenesis because of abnormal
hypoxia-associated occluded microvessels, which is also partially responsible for keloid resistance to
radiation therapy . It was observed that the central area of keloid is severely ischemic, exhibiting higher
[37]
hypoxia-inducible factor-1a (HIF-1a) expression and lower vascular density than their marginal areas and
normal skin borders [38,39] . The HIF-1α is also involved in the inflammatory process by regulating angiogenesis
and inflammatory cell functions [40-42] . Blocking HIF-1 signal pathways by either 2ME2 or HIF-1α siRNA
[37]
has been shown to successfully increase the radiation-induced apoptosis in keloid fibroblasts . Hypoxia
can also drive the transition of human dermal fibroblasts to a myofibroblast-like phenotype via the
[36]
transforming growth factor -β1/SMAD3 pathway , and increase the expression of vascular endothelial
growth factor (VEGF) in keloids [35,38] . Glycolysis, the major glucose metabolic pattern for keloid tissues,
could also interact with hypoxia and promote the lactate accumulation, resulting in excessive collagen
[43]
production and fibrogenic activities .
Stress hormones might influence keloid formation by dysregulating the immune system and
inflammation
The classical model of wound healing involves three distinct but overlapping phases that chronologically
occur as the inflammatory, the proliferative, and the remodeling phases. Disturbance of these processes,
especially the prolonged and excessive inflammatory reactions could lead to an increase of fibroblast
activities and excessive extracellular matrix (ECM) production . The available evidence indicates that
[44]
malfunction of the immune system and inflammation might be involved in keloid formation. Keloid
[45]
tissues are highly infiltrated with various immune cells, immunoglobulins and complements , as well as
growth factors, cytokines and proteases, such as IL-6, tumor necrosis factor (TNF), transforming growth