Zifei Li, Qingliang Liu, Xiaojun Wang*, and Jie Luan*

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The Characteristics of Blood Supply and Tissue Hypoxia in Pathological Scars

Zifei Li1, Qingliang Liu2, Xiaojun Wang2*, and Jie Luan1*

1Department of Aesthetic and Reconstructive Breast Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, China2Division of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China

Blood supply is believed to be an important aspect in the development of pathological scars. However, there are controversies about vascular distribution, vascular structure and blood flow inpathological scars. Additionally, hypoxic microenvironment plays an important role in the vascularization of pathological scar tissues, and hypoxic conditions can be reflected by metabolic indexes and some cytokines. Furthermore, the correlation between blood supply and tissue hypoxia is controversial. The aim of this article is to review the literature on the characteristics of blood supply and tissue hypoxia in pathological scars, from which we can see pathological scars have unique characteristics of blood supply that are closely associated with tissue hypoxia. Moreover, development in the treatment of pathological scars is herein reviewed.

pathological scar; hypertrophic scar; keloid; blood flow; hypoxia

Chin Med Sci J 2017; 32(2):113-118. DOI:10.24920/J1001-9294.2017.014

ATHOLOGICAL scars include hypertrophic scar and keloid. They influence appearance and even cause functional disturbance, and place tremendous physiological and psychological burdens on patients. Therefore, pathological scars have been a challenge in plastic surgery and the focus of research. Blood supply is believed to be an important aspect in the development of pathological scars, and has thus attracted more attentions in recent years. However, there are controversies about blood supply in pathological scars. Hereby we summarized the advances of research on the blood supply in pathological scars, and explored future research directions.

VASCULARITY OF PATHOLOGICAL SCARS

Vascular distribution of pathological scars

Vascular distribution of pathological scars is determined by vascular quantity and vascular type. In terms of quantity, papillary and reticular layers of hypertrophic scars and keloids have more blood vessels than normal skin.1Compared with normal scars, the number of blood vessels is markedly lower in hypertrophic scars, and even more lower in keloids.2Vascular distribution within pathological scar tissues has been controversial yet. Recently, Ryoma Touchifound that the central areas of keloids exhibited lower vascular density than the marginal areas. Besides, compared to the hypertrophic scars, keloids was noted to have lower vascular density in the central areas and higher vascular density in the marginal areas.3The characteristics of the vascular type within keloid tissues have received much attention. Some researchers divided keloids into different areas, including zone of hyalinizing collagen bundles (HCBs), fine fibrous area, area of inflammation, zone of dense regular connective tissue, nodular fibrous area, and area of angiogenesis.4HCB zone is the area where blood vessels, mainly venules, are distributed scarcely. Capillaries and postcapillary venules in the fine fibrous areas, which surround the HCB zone, are the main visible vascular structure. Compressed and degenerated small veins mainly distributed in the inflammation area, whereas severely compressed microvessels mainly scattered among bundles in the dense regular connective tissue zone. In the nodular fibrous area, degenerated microvessels are present in the wide extracellular spaces inside or outside the nodules. The angiogenesis at the junction area of keloids and normal skin, as well as junction area of keloids and papillary dermis, are characterized by progressively differentiated small blood vessels and small neurovascular bundles. In the nodules, there exists some islets of angiogenesis, where the vessels are of less severity in pathological changes and persist differentiating ability into arterioles.4

Vascular structure of pathological scars

The vascular structure of pathological scars has different manifestations between hypertrophic scars and keloids. In terms of spatial vascular structure, blood vessels within hypertrophic scar tissues have a structure perpendicular to the skin surface, whereas those within keloid tissues present a typical dispersed, extended vascular structure.5,6The diameter or patency of the blood vessels of pathological scar remains controversial. Thaísused stereological methods to obtain information on pathological scar tissues with a microscope, and proposed that the blood vessels within the pathological scars were dilated compared with those in normal skin and normal scars.1The reason for the dilatation of blood vessels may be associated with the keratinocyte mediation of vasodilation through nitric oxide-dependent mechanisms under hypoxia.7On the other hand, the bulk of studies investigating keloid blood supply found that the lumen of microvessles is occlusive.8One of the causes of vascular occlusion is the excessive proliferation of endothelial cells.6Under an electron microscope, marked bulging of the endothelial lining into vascular lumens was visible in keloids.9The second cause is the intense proliferation of fibroblasts. Before the development of pathological scars, fibroblasts have already begun to proliferate.10Fibroblasts increasing in number compresses the blood vessels, causing vascular distortion and narrowing. The third cause is the uncontrolled collagen production by fibroblasts in the extracellular matrix, which results in substantial collagen deposition in the microvasculature11, 12and further luminal stenosis. For a single vessel, vascular structures within the hypertrophic scars and keloids are also different. Compared with the blood vessels in hypertrophic scars, those in keloids are smaller in diameter and flatter in shape.13In keloid tissues, vascular structures also vary among different areas. Blood vessels in central area are relatively flatter than those in marginal area.13

Blood flow in pathological scars

In recent years, laser Doppler techniques have been widely used in studies on skin blood flow, such as laser Doppler flowmetry (LDF), laser Doppler perfusion imaging, and laser speckle contrast imaging (LSCI).14-17These techniques are increasingly used in the detection of blood flow in pathological scars. Blood flow measurements are related to the blood flow velocity and red blood cell concentration. Timar-Banuused LDF technique and found that, the blood flow in pathological scars was greater than that in normal skin.18Qingliang Liuused LSCI technique and found that the blood flow in the adjacent skin surrounding keloid tissues was greater than that in nonadjacent skin tissues.15Blood flow also changes with the progression of pathological scars. Ehrlich’s study showed that, at 16–18 weeks after wound closure, the blood flow in hypertrophic scars was still three times higher than in normal skin and four times greater than in normal scars.19

TISSUE HYPOXIA IN PATHOLOGICAL SCARS

Although the pathogeneses of pathological scars remain unclear, studies have suggested that the hypoxic microenvironment may be one of the responsible factors. Recently, there have been a growing number of studies claiming that the hypoxic microenvironment plays an important role in the vascularization of pathological scar tissues.8, 20

Metabolic manifestations of tissue hypoxia

The oxygen partial pressure within tissue is a direct index reflecting tissue hypoxia. Studies on the oxygen partial pressure within pathological scar tissues have mostly focused on investigating hypertrophic scar tissues. Studies found that, compared to normal skin, hypertrophic scars have lower oxygen partial pressure and higher carbon dioxide partial pressure, suggesting that hypertrophic scar tissues are in a hypoxic state.21Sloan's measurement with a dual-port medical mass spectrometer found significant reduced oxygen partial pressures (13.1±2.9 mmHg) in hypertrophic scars of burn patients compared to normal dermis.21Zheng's study further demonstrated that transcutaneous pressure of oxygen within hypertrophic scars decreased gradually when scars transit from early stage to regressive stage, and then returned to near- normal levels upon scar maturation. These results suggest that during the process of regression and maturity, with apoptosis of most cells in hypertrophic scars, the collagen gradually hydrolyze, new blood vessels gradually open, and tissue oxygen level gradually return to near-normal levels.22

Lactate is a product of cellular anaerobic glycolysis that can be used as an indirect index of tissue hypoxia. Studies on the lactate level in pathological scars mainly focus on keloid tissues. Iwakiri reported that the lactate concentration in keloids was higher than that in the normal skin or normal scars. In normal scar tissues, lactate content decreases with the extension of posttraumatic time; whereas in keloids, the lactate content of posttraumatic tissue maintained at a high level continuously. Compared with hypertrophic scars, lactate content in keloids is higher and maintained at high level for a long time, suggesting persistent anaerobic glycolysis within keloids.2

ATP is produced mainly through the oxidative phosphorylation of glucose in the mitochondria under aerobic conditions, and partially through anaerobic glycolysis. There are studies that investigated in the hypoxia and metabolic status of pathological scar tissues through changes of ATP concentration within the tissues. Some researchers measured the tissue ATP levels and found that, with inhibiting glycolysis, there is more remarkable inhibition of ATP synthesis within keloid fibroblasts (KFs) than within normal fibroblasts (NFs), but there is more ATP production within KFs in the hypoxia and hypoxia-mimetic states.23These results indicate that ATP synthesis is dependent on glycolysis in KFs, but on mitochondrial oxidative phosphorylation in NFs. Therefore, ATP can be considered as an index for active metabolism of pathologic scar tissues under hypoxia. Uedastudied the difference of ATP content in keloids, red hypertrophic scars, pink hypertrophic scars, and atrophic white scars, and found there was no significant difference in ATP concentration between red hypertrophic scars and keloids. Furthermore, compared with pink hypertrophic and atrophic white scars, the ATP concentration in keloids was higher and maintained at high levels for a long time.24

Blood supply-related cytokines in tissues under hypoxic conditions

HIF-1 is an important regulator for cell survival under hypoxic conditions, whereas it is rapidly hydroxylated and degraded under normoxic conditions.25Under hypoxic conditions, HIF-1 accumulates through dimer formation and enters the nuclei to promote the expression of a series of genes, thereby adapting cells and tissues to the hypoxic environment. Studies on mechanisms of pathological scars in relation to HIF-1 had focused on the expression of HIF-1 in keloid tissues. Zhangfound that HIF-1 expression is upregulated in keloids compared with peripheral normal skin.26A study of hypertrophic scar tissues found the expression of HIF-1 increased firstly and then decreased with the progression of the scar, which indicated moderate to severe hypoxia.22This is because, when the increase of hypoxia reaches a certain threshold level, HIF-1 no longer increases accordingly, but decreases instead. Such decrease is associated with inhibition of HIF-1 expression by the increased p53 under hypoxia.27

VEGF can promote proliferation of endothelial cells and induce angiogenesis, which plays important roles in wound healing. Hypoxia is an important mechanism for inducing VEGF expression.3van der Veer found no significant difference in VEGF expression between hypertrophic scar tissues and normotrophic scar tissues.28However, VEGF was found to be highly expressed in keloid tissues.29Moreover, Steinbrech found that hypoxia could stimulate upregulating of VEGF expression in KFs.30Interestingly, Ryoma Touchi’s study showed that there is no significant difference in VEGF expression between central and marginal areas.3VEGF was not only highly expressed in local keloid tissues, but also elevated in serum in patients with keloids scars compared with normal population.31

TGF-β family members have important roles in embryonic development and regulation of tissue homeostasis.32Hypoxia may facilitate high TGF-β1 expression by mediating the TGF-β1/Smad signaling pathway.33Moreover, the pathway is closely related to the formation of pathological scars. Many studies have demonstrated that TGF-β1 can provide signal substances for normal healing during the early phase of scar healing, whereas the expression level of TGF-β1 after epithelial healing is directly proportional to the degree of scar hyperplasia.34Some studies have shown that 90% of TGF-β1 expression in pathological scar tissues is from the epidermis, whereas the proportion is 60% in normal postoperative scars and only 20% in normal skin. This suggests the active role of keratinocytes in keloid fibrosis. In addition, the shorter the interval time from wounding, the higher the expression of TGF-β1 in the pathological scar dermis, which suggests that VEGF may play an important role in the early stages of pathological scar formation.35

Relationship between cytokines

Pathological scar tissues produce a series of adaptive responses in a hypoxic environment, during which HIF-1 plays a pivotal role.22In the hypoxic state, HIF-1 enters the nucleus, binds to the hypoxia responding elements, and regulates the transcription and expression of its downstream factors such as VEGF. There also exists a synergism between these cytokines. For example, TGF-β can regulate VEGF gene expression at the transcriptional level synergistically with HIF-1.36According to Masao's study, exogenous TGF-β1 can directly stimulate VEGF expression in KFs, and anti-TGF-β1 antibodies can inhibit the expression of VEGF.37These cytokines cooperate with one another and are jointly involved in the regulation of blood supply formation of pathological scars in hypoxic environments.

CORRELATION OF BLOOD SUPPLY AND TISSUE HYPOXIA IN PATHOLOGICAL SCARS

Abundant blood supply but insufficient oxygen supply

Whether the blood supply is sufficient or not is closely related to the metabolic status of tissues, which cannot be truly assessed simply by indices such as vascular density and blood flow. The hypoxic state within tissues is a comprehensive index of blood oxygen supply and tissue oxygen consumption; thus, the presence or absence of tissue hypoxia can indirectly reflect the adequacy of the tissue blood supply. A variety of evidences have indicated that the hypoxic state in pathological scar tissues is caused by insufficient oxygen supply in spite of an abundant blood supply.

The relative lack of oxygen is partially due to insufficient supply of oxygen through the blood vessels. Despite the enhanced vascular density, increased blood flow, and rich blood supply within pathologic scar tissues, vascular occlusion in tissues prevents the effective exchange of oxygen from blood into tissues. As for the causes of vascular occlusion, aside from the aforementioned vascular structural change, endothelial cell malfunction caused by hypoxia may also exacerbate the occlusion and hypoxia.38A study indicated that, the vascular caliber was larger in pathological scars; even with the increased blood flow in the tissue, blood supply doesn’t actually reach the periphery;13and the ineffective oxygen exchange through vascular walls may still result in hypoxia.

On the other hand, hypoxia is also associated with increased oxygen consumption in pathological scar tissues. Studies have shown that oxygen consumption of keloid tissue is higher than that of mature scars,39so that even if blood flow is good and the blood supply is rich within the keloid tissues, the oxygen supply is relatively insufficient owing to increased tissue oxygen consumption, thus the internal environment is still in a relatively hypoxic state.22

Formation of mutual cause-effect relationship between tissue hypoxia and blood supply in patholo- gical scars

It is unclear whether tissue hypoxia is the initial mechanism for blood supply formation in pathological scars. Some researchers believe that vascular deformation in pathological scars is a causative factor, and that microvascular occlusion leads to tissue hypoxia.40Moreover, the gradual accumulation of vascular endothelial cells, fibroblasts and collagens aggravates the vascular deformation and occlusion, forming a cycle with hypoxia, and thereby leading to gradually exacerbated early hypoxic state. In addition, cytokines produced during tissue adapting to hypoxia are important promoters of angiogenesis. For example, upregulation of the expression of VEGF, Ang-1, and periostin can promote angiogenesis.40Tissues produce a variety of proangiogenic factors in the hypoxic state to induce a hypoxia-vascular hyperproliferation-hypoxia cycle. The vascular hyperproliferative state may be an important factor for the neoplastic infiltrative growth of keloids.

Nevertheless, hypoxia is not increasingly intensified, and there may be dynamic changes in the oxygen consumption of tissues. According to a study, severe hypoxia inhibits VEGF expression in scar tissues. Severe hypoxia and malnutrition in scar tissues play key roles in inducing the regression of hypertrophic scar through fibroblast inhibition and cell apoptosis.41

PERSPECTIVES OF FURTHER RESEARCHE

Many controversies still exist in the study of blood supply in pathological scars. For example, the quantity and openness of blood vessels in different areas of keloid and hypertrophic scar are still inconclusive. Moreover, the mechanisms for blood supply formation in pathological scars, such as expression of the initial factor, cytokines and relevant pathways, are still unclear and need further study. At present, invasive treatments for pathological scars, especially keloids, are primarily surgery and postoperative radiotherapy. A study has shown that HIF-1 enhances the tissue’s resistance to radiotherapy by promoting angiogenesis and strengthening glycolysis.42The radiotherapy-resistant mechanism of pathological scars needs further investigation. Targeted therapy based on the blood supply for pathological scars still has room for further development.

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for publication June 27, 2016.

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