The Vascular Involvement in Soft Tissue Fibrosis—Lessons Learned from Pathological Scarring

Abstract

Soft tissue fibrosis in important organs such as the heart, liver, lung, and kidney is a serious pathological process that is characterized by excessive connective tissue deposition. It is the result of chronic but progressive accumulation of fibroblasts and their production of extracellular matrix components such as collagens. Research on pathological scars, namely, hypertrophic scars and keloids, may provide important clues about the mechanisms that drive soft tissue fibrosis, in particular the vascular involvement. This is because these dermal fibrotic lesions bear all of the fibrotic characteristics seen in soft tissue fibrosis. Moreover, their location on the skin surface means they are readily observable and directly treatable and therefore more accessible to research. We will focus here on the roles that blood vessel-associated cells play in cutaneous scar pathology and assess from the literature whether these cells also contribute to other soft tissue fibroses. These cells include endothelial cells, which not only exhibit aberrant functions but also differentiate into mesenchymal cells in pathological scars. They also include pericytes, hepatic stellate cells, fibrocytes, and myofibroblasts. This article will review with broad strokes the roles that these cells play in the pathophysiology of different soft tissue fibroses. We hope that this brief but wide-ranging overview of the vascular involvement in fibrosis pathophysiology will aid research into the mechanisms underlying fibrosis and that this will eventually lead to the development of interventions that can prevent, reduce, or even reverse fibrosis formation and/or progression.

Systemic factors that shape cutaneous pathological scarring

“…Multiple lines of evidence show that the blood vessels are deranged in cutaneous pathological scars. 4,5 In particular, they are very dense at the inflamed periphery of the pathological scar yet largely absent in the inactive center. 6,7 In keloid patients, the systemic balance between proangiogenic factors and anti-angiogenic factors is distorted, as indicated by the altered circulating levels of vascular endothelial growth factor (VEGF), endothelial progenitor cells (EPCs), and endostatin, as follows.…”

Primary Ciliary Signaling in the Skin—Contribution to Wound Healing and Scarring

“…Ogawa (2017) suggested that keloids and hypertrophic scars are derived from an abnormal inflammatory reaction in the skin since proinflammatory factors, including IL-1α, IL-1β, IL-6, and TNF-α, are associated with keloid formation. Additionally, disorders of vascular cells can cause pathological scars since inflammation stimulates excessive angiogenesis, endothelial disorder, and vascular hyperpermeability (Huang and Ogawa, 2020). It has been proposed that mechanical tension promotes the dysregulation of cell proliferation and apoptosis during wound healing and may result in keloids and hypertrophic scars (Pozos, 2014;Harn et al, 2019;Ogawa, 2019).…”

Comprehensive Analysis of Circular RNA Expression in ceRNA Networks and Identification of the Effects of hsa_circ_0006867 in Keloid Dermal Fibroblasts

“…Regarding downregulated circRNAs, morphogenesis of the epithelium showed the highest relevance in GO analyses. It is well known that epithelial cells transform into myofibroblasts and fibroblasts via the epithelialmesenchymal transition (EMT) process (Yuan et al, 2019;Huang and Ogawa, 2020). Chen and the co-workers (Chen et al, 2020) found that circ_0008450 promotes proliferation and processing in human keratinized epithelial cells through the TGF-β/Smad/Runx3 axis.…”

“…Keloids are benign skin fibroproliferative tumors unique to humans characterized by aggressive fibroblast proliferation, excessive accumulation of extracellular matrix (ECM) (e.g., collagen I and III), long-term continuous fibrosis, and abnormal inflammatory stimuli (Yan et al, 2021;Zhang et al, 2021). Keloids show various cancer-like features, such as aggressive proliferation beyond the original boundary, lack of spontaneous regression, and vascularization ability (Huang and Ogawa, 2020). As a common clinically challenging disorder, keloid formation generally follows wounding, such as burns, surgery, laceration, or other damage to the dermis (Davies et al, 2021).…”