Elevated Vascular Endothelial Growth Factor in Keloids: Relevance to Tissue Fibrosis

Abstract

Excessive scar or keloid shares common features of a benign dermal growth. Yet, in contrast to malignant tumor, a keloid does not expand beyond the dermis. What triggers the continuing growth of a benign lesion? Deficient or overabundant levels of vascular endothelial growth factor have been reported to contribute to impaired or excessive wound healing. Although numerous studies have examined the pathophysiology of impaired wounds, little information has been provided on mechanisms of exuberant healing. The molecular basis of keloid formation is governed by the interplay of cellular signaling pathways, specific target gene activation, and the nature of the microenvironment. Recent works have demonstrated an accumulation of hypoxia-inducible factor-1α protein in freshly biopsied keloid tissues, thus providing first evidence that a local state of hypoxia exists in keloids. Our findings and the findings of others support at least two plausible mechanisms implicated in the development of fibrotic wounds, a state of ongoing fibroplasia or inflammation and an excessive accumulation of extracellular matrix. This article will review recent works examining the potential role of vascular endothelial growth factor in keloid pathogenesis with particular focus on its involvement in the two proposed pathological processes, a prolonged inflammation and an altered balance in extracellular matrix metabolism.

Increased vascular endothelial growth factor may account for elevated level of plasminogen activator inhibitor-1 via activating ERK1/2 in keloid fibroblasts

“…These results support the hypothesis that an altered balance of activator and inhibitor activities in the plasminogen system, in particular, an overexpression of PAI-1, may partly contribute to keloid formation and tissue fibrosis (40). Moreover, numerous studies revealed an abundant accumulation of growth factors and cytokines in keloids (1,31,32,63,64), some of which can be upregulated by hypoxia (50). These factors, such as insulin and insulin-like growth factors (IGFs) (5,12), fibroblast growth factor (FGF) (25), plateletderived growth factor (PDGF) (47), transforming growth factor (TGF), and tumor necrosis factor-␣ (TNF-␣) (49), in combination with local tissue hypoxia (16,17,27,66), may play an essential role in the regulation of PAI-1 expression.…”

“…Previous studies described an abundance of growth factors and cytokines (31,32,63,64) in the keloid milieu. During the inflammatory stage of wound healing, macrophages and neutrophils are activated and proinflammatory cytokines are released; among these is VEGF.…”

Association of HLA-DQA1 and DQB1 alleles with keloids in Chinese Hans

“…They are thick scar tissue of human skin, which have escaped the boundaries of the original wound to invade the surrounding normal skin. However, they are limited to the dermis unlike a malignant tumour [3]. Keloids were first described centuries ago in the Smith Papyrus, later in 1770 by Retz and in 1806 by Alibert, who proposed the current name [4].…”

Influence of the Human Leukocyte Antigen Complex on the Development of Cutaneous Fibrosis: An Immunogenetic Perspective

“…In addition, the degree of keloid scar tissue bears little or no resemblance to the initial underlying injury, with trivial trauma resulting in severe, abnormal scar tissue (7). Although keloids have been previously reported to occur spontaneously (1,7,56,57), it is likely that these lesions had been caused by trivial or over-looked injury, such as insect bites or razor cuts (7,52). As such, the early classification of keloids into two groups; namely "true" keloids (spontaneous lesions devoid of previous trauma) and "false" keloids (arising from an initial trauma) has been entirely rejected (7).…”