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. 2020 Oct 11;17(6):1902–1908. doi: 10.1111/iwj.13480

Plasminogen activator inhibitor‐1: a potential etiological role in livedoid vasculopathy

Yimeng Gao 1, Hongzhong Jin 1,✉
PMCID: PMC7948802  PMID: 33043622

Abstract

Livedoid vasculopathy (LV) is a chronic, recurrent skin disorder with unknown aetiology and pathogenesis that seriously affects the quality of life of people who suffer from it. Plasminogen activator inhibitor (PAI)‐1 is a primary inhibitory component of the endogenous fibrinolytic system in blood coagulation. PAI‐1 also plays a role in many other physiological processes and activities, including thrombosis, fibrosis, wound healing, angiogenesis, inflammation, cell migration, and adhesion. Enhanced expression and genotype polymorphism of PAI‐1 have been observed in LV patients. In this review, we summarise the known functions of PAI‐1 with emphasis on the roles that PAI‐1 probably plays in the pathogenesis of LV, thereby illustrating that PAI‐1 represents a potential LV biomarker and therapeutic target for treating LV.

Keywords: aetiology, plasminogen activator inhibitor 1, vascular diseases

1. INTRODUCTION

Livedoid vasculopathy (LV) is a benign and chronic skin disease that predominantly affects lower extremities and dorsal feet. The typical skin lesions of LV are recurrent livedo reticularis, purpura, erythema, necrotic macules, painful ulcers, and atrophic porcelain satellite scars with summer exacerbations (Figure 1). Feldaker et al described the entity in 1955 and named the disorder livedo reticularis with summer ulcerations. 1 In histology, intraluminal thrombosis, noninflammatory endothelial proliferation, and segmental hyalinization in dermal vessels are characteristic manifestations of LV, whereas signs of vasculitis are often absent or secondary. LV is defined purely as a thrombo‐occlusive vasculopathy, mainly involving cutaneous capillary microcirculation. The occlusion and thrombosis in cutaneous blood vessels finally results in ischemia and infarction in the cutaneous form. 2

FIGURE 1.

FIGURE 1

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A–C, Livedo reticularis on lower extremities. D, Atrophic porcelain satellite scars and pigmentation on dorsal feet and ankle. E, Painful ulcers on both ankles

The aetiology of LV remains unclear. Although histological findings of intraluminal thrombosis and heterogeneous coagulation abnormalities in LV patients provide evidence of procoagulant and hypercoagulability mechanisms, 3 the specific pathogenesis and pathway remain unresolved. Hypercoagulability, caused by hereditary and acquired deficiency of anticoagulants or increased and activated procoagulant components, occurs frequently in some LV patients. Thrombotic factors including a decrease in the activity of protein C, protein S, and anti‐thrombin, lupus anticoagulant, antinuclear antibodies, anticardiolipin antibodies, elevated homocysteine levels and lipoprotein(a), factor V Leiden mutation, prothrombin G20210A gene mutation, and methylenetetrahydrofolate reductase (MTHFR)‐C677T polymorphism were proved to participate in the hypercoagulability of LV. 3 , 4 Additionally, some systemic diseases like connective tissue diseases, carcinoma and malignancy, venous insufficiency, deep venous thrombosis, cerebrovascular accident, and peripheral arterial occlusive diseases leading to thrombophilic states were found to coexist in LV patients. 3

Plasminogen activator inhibitor (PAI)‐1 is an inhibitor of the endogenous fibrinolytic system in blood coagulation and has gradually drawn attention because of its potential role in the pathogenesis and mechanism of LV. PAI‐1 4G/5G gene polymorphism and elevated plasma levels of PAI‐1 have been detected in venous thromboembolism, and PAI‐1 may be a suitable biomarker for assessing the risk of venous thromboembolism. 5 In recent years, Agirbasli et al observed that increased mRNA expression of PAI‐1 in cutaneous lesions of LV was highly associated with histological findings of ulcers. 6 Moreover, LV patients with PAI‐1 promoter homozygosity (4G/4G) responded well to tissue plasminogen activator infusion therapy. 7 , 8 Thus, a possible link between PAI‐1 activity and LV skin lesions is suspected.

The aim of this review is to explore the potential etiological role of PAI‐1 in the pathogenesis and mechanism of LV.

2. BIOLOGICAL AND GENETIC BACKGROUND OF PAI‐1

2.1. Molecular structure and biological function of PAI‐1

As a member of the serine proteinase inhibitor superfamily, PAI‐1 is a main component of the plasminogen‐plasmin system that inhibits the tissue‐type plasminogen activator (tPA) and urokinase‐type plasminogen activator (uPA). Composed of 379 amino acids, PAI‐1 is a single‐chain glycoprotein with a tertiary structure containing nine alpha‐helices and three beta‐sheets. 9 Although PAI‐1 is synthesised and secreted in active forms by endothelial cells, adipocytes, fibroblasts, hepatocytes, and cardiomyocytes, 10 platelets are the major source for the circulating plasma PAI‐1 level with rapid conversion to a latent form. 11 PAI‐1 may sustain the capability of reactivation when encountering different stimuli like vascular injury. 12

PAI‐1 suppresses the fibrinolysis system and promotes coagulation by binding to tPA or uPA to form irreversible complexes. 13 Besides its basic function of fibrinolysis inhibition, PAI‐1 exhibits and regulates pleiotropic functions and is involved in a variety of physiological activities and diseases, including thrombosis, cardiovascular disease, metabolic disturbance, fibrosis, cell migration and adhesion, wound healing, angiogenesis, inflammation, cancer development, and reproductive processes. 14 , 15 , 16

2.2. PAI‐1 4G/5G gene polymorphism

Located on chromosome 7q, 17 the PAI‐1 gene demonstrates 4/5‐guanine‐tract (4G/5G) polymorphism in the promoter‐675 region by deletion or insertion of guanine nucleosides. 18 The PAI‐1 genotype possesses genetic variation so that the expression of PAI‐1 is influenced by homozygosity or heterozygosity. Previous sequence and molecular biology studies 18 , 19 revealed that the 4G allele genotype is responsible for higher PAI‐1 activity because PAI‐1 binds to nuclear proteins as enhancers regulating PAI‐1 gene transcription, and the expression level of PAI‐1 is highest in the 4G/4G genotype, intermediate in the 4G/5G genotype, and lowest in the 5G/5G genotype. The PAI‐1 levels in the 4G/4G genotype were estimated to be approximately 25% higher than those in the 5G/5G genotype. 18

PAI‐1 gene 4G/5G polymorphism is associated with many diseases, including venous thromboembolism, 5 , 19 polycystic ovary syndrome, 14 asthma, 20 myocardial infarction, 21 and LV. Some LV patients were successfully treated with tPA therapy, and sequencing results revealed that their PAI‐1 genotypes were homozygous (4G/4G). 7 , 22 PAI‐1 genotypes may be dependent on ethnicity, according to genetic mutations and differences. In genotype testing for promoter PAI‐1 4G/5G polymorphism conducted in Turkey, 25% of the subjects demonstrated homozygosity (4G/4G), whereas over half of the subjects displayed heterozygosity (4G/5G). 23 In contrast, the results of PAI‐1 4G/5G genotyping and allele testing in Taiwan, China were not significant. 24

3. POTENTIAL MECHANISM OF PAI‐1 IN THE PATHOGENESIS OF LV

3.1. Thrombosis

Besides genotype polymorphism, further research examining the expression of PAI‐1 in plasma, skin lesions, and its stability have been performed for LV patients. The significantly increased PAI‐1 antigen levels, moderately elevated PAI‐1‐specific activity levels and mRNA expression of PAI‐1 was, respectively, detected in plasma and skin lesions of LV patients, 6 , 23 and PAI‐1 increases were detected in the extracellular matrix and perivascular areas by immunostain qualitative analysis. 23 Newly secreted PAI‐1 is in its active form and spontaneously changes to the latent state with a half‐life of 1 to 2 hours. 25 Research examining the stability of PAI‐1 revealed that the remaining PAI‐1 specific activity in LV patients was much higher than healthy controls after exposure for 16 hours at room temperature, indicating that PAI‐1 in LV patients displayed enhanced functional stability. 23

Examination of the recognised pathogenesis of LV, i.e., endothelial cell plasminogen activation, platelet dysfunction, and fibrin accumulation, has yet to be linked with the hypercoagulability state, which leads to cutaneous vessels intraluminal thrombosis. 2 The formation of fibrin and thrombus causes ischemic infarction because of insufficient oxygen supply to tissues. 2 The fibrinolysis system is a crucial protective mechanism that inhibits thrombosis and closely correlates with the balance of platelet, fibrinolysis, and coagulation. The interaction of PAI‐1 with tPA and uPA to form complexes in a cascade‐like process with vitronectin (VN) maintaining its active form suppresses their interaction with plasminogen, thus, inhibiting the activation of the endogenous fibrinolytic system and increasing the risk of thrombosis.

Epidemiology investigation showed that overexpression of PAI‐1 and its enhanced activity was highly correlated with thrombotic disease. The effect of PAI‐1 has been shown to be associated with thrombosis and hypercoagulability both in vivo and in vitro. In the 10‐year prospective longitudinal follow‐up of patients with diabetes developing a lower extremity arterial disease, it was found that baseline tPA activity may be a predictor for the onset of early lower extremity arterial disease. 26 The time for PAI‐1‐deficient photochemically vascular injured mice to develop occlusive thrombosis in carotid arteries was much longer than wild‐type mice that suffered from the same photochemically vascular injury. 27 Pressure ulcers that present with the same ulcerative skin lesions as LV are considered to be an irreversible ischemic injury. Although the aetiology and mechanism of LV have not been fully characterised, thrombosis, especially thrombosis caused by external force resulting in tissue hypoxia, is becoming a major event of LV. 28 Both fibroblasts from young ulcer bed and senescent pressure ulcer tissue generated a higher level of PAI‐1 expression when compared with that of young normal skin fibroblasts, especially in senescent fibroblasts. 29 The upregulation of mRNA expression in a compression mouse model was clearly altered by the application of the hypoxia inducible factor‐1 (HIF‐1) inhibitor rather than Ticlopidine hydrochloride, a thrombosis inhibitor. 30 This observation indicates the participation of PAI‐1 in HIF‐1 enhanced thrombosis and HIF‐1 may be a regulatory factor in PAI‐1‐induced thrombosis. In turn, the siRNA‐mediated PAI‐1 gene silencing promoted the recanalization of venous thrombosis by a reduction in PAI‐1 expression concomitant with an increase in vascular endothelial growth factor (VEGF) expression to improve lumen‐like structures. 31

3.2. Cell adhesion, migration, and angiogenesis

The histologic manifestation of LV reveals significant proliferation of endothelial cells and intraluminal thrombosis in dermal vessels, and intraluminal thrombosis is often accompanied with the establishment of collateral circulation and angiogenesis. However, the role of PAI‐1 in the pathway or mechanism of angiogenesis, endothelial cell proliferation, and perivascular inflammation cell adhesion in LV requires further in vivo and in vitro research efforts. Previous studies have shown that the function of PAI‐1 in regulating angiogenesis and cell adhesion involves mainly extracellular matrix proteolysis. In recent years, researchers have highlighted the mechanism of extracellular proteolysis in the plasminogen activation system. As an essential part of tissue remodelling and wound healing, impaired extracellular proteolysis is involved in the pathogenesis of chronic skin ulcers. tPA contributes mainly to fibrinolysis because of its higher affinity towards fibrin, whereas the plasminogen activator uPA regulates localised cell‐related proteolysis and moves to the cell membrane where it binds to the specific uPA receptor present on the cell surface. 32

The plasminogen activation system is altered in non‐healing leg ulcers when compared with that of well‐granulating wounds. 33 uPA and its receptor both reside on the cell membrane in many types of cells, and PAI‐1 initiates the process of intracellular signalling by connecting proteins on the membrane surface. 34 The bell‐shaped and angiogenesis response of endothelial cells when stimulated with varying concentrations of recombinant PAI‐1 has been described. 35 , 36 Exposure to a low concentration of PAI‐1 (i.e., 1 ng/mL) may promote wound closure, whereas a higher concentration of PAI‐1 (i.e., 1000 ng/mL) causes anti‐migratory effects. 35 In gene‐inactivated mice, PAI‐1‐deficiency caused a complete loss of angiogenesis. By supplementing with exogenous recombinant PAI‐1, the effect of microvessel outgrowth demonstrated that PAI‐1 is proangiogenic at physiological concentrations and antiangiogenic at higher concentrations. 36

However, in tumour progression, there is convincing evidence that PAI‐1 regulates cell invasion and angiogenesis. As an independent negative prognostic factor for multiple cancers, PAI‐1 in tumour tissue contributes to proliferation of endothelial cells and tumour angiogenesis via upregulation of VEGF expression. 37 In PAI‐1 deficient mice, tumour cell invasion, metastasis, and angiogenesis were observed after transplanting malignant keratinocytes, and tumour cell invasion and angiogenesis were suppressed by injection of a PAI‐1 supplement. 38

3.3. Inflammation

The role of an inflammatory factor in the pathogenesis of LV remains controversial. Although histological findings indicate predominately noninflammatory cell infiltration, endothelial proliferation and the absence of vasculitis, it remains plausible that an inflammatory factor plays a secondary role in the pathogenesis of LV2 because elevated levels of interleukin‐2 and P‐selection, both indicators of platelet and lymphocyte activation, were present in LV. 39 Moreover, in some clinical studies, anti‐inflammatory medications remain indispensable for management of the acute and ulcerative stage, 40 , 41 and our previous study observed the efficacy of etanercept in LV, 42 supporting further evidence for the involvement of a concomitant inflammatory process.

PAI‐1 has been shown to be linked with various inflammatory diseases, such as asthma, chronic obstructive pulmonary disease, and sepsis. 20 , 43 Cytokines and recruitment of inflammatory cells to a certain degree reflects localised inflammation. Cytokines such as tumour necrosis factor‐alpha and interleukins are partly regulated by PAI‐1. Increases in the levels of inflammatory markers like C‐reactive protein and interleukin‐6 were found to correlate with elevated levels of PAI‐1 and other changes in coagulation for type 2 diabetes mellitus patients with microvascular complications, suggesting a close relationship between PAI‐1 and inflammation. 44 Additionally, the reduced recruitment of neutrophils to lungs during infection was detected in PAI‐1‐deficient mice models, whereas the overexpression of PAI‐1 in healthy control mice led to an influx of inflammatory cells. 45 PAI‐1 contributes to the regulation of the lipopolysaccharide‐induced inflammation response through activation of autophagy and probably involves the Toll‐like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD‐2) pathways. 46 After PAI‐1 gene silencing, the levels of biomarkers for autophagy microtubule‐associated protein 1 light chain 3 (LC3) and Beclin1 decreased, and the mammalian target of rapamycin (mTOR) was upregulated in NR8383 rat macrophages stimulated with lipopolysaccharides. 47

4. POTENTIAL MECHANISM FOR ELEVATED PAI‐1 LEVELS IN LV

4.1. Binding cofactor VN

VN is an acute‐phase‐reactant plasma protein that interacts with PAI‐1. Interaction and binding of VN to PAI‐1 mainly around alpha‐helix E and alpha‐helix F sites not only stabilises PAI‐1 in the active conformation but also influences both function and expression of VN, which is involved in fibrinolysis, hypercoagulability, cell adhesion, and vascular remodelling. VN contains two PAI‐1 binding sites: a high‐affinity binding site located in the N‐terminal region and a low‐affinity site located in the C‐terminal region of the protein. 48 The high affinity site is the major PAI‐1 binding site, whereas the low‐affinity site forms a larger PAI‐1/VN complex. 48 VN gene expression is regulated by PAI‐1 in vascular smooth muscle cell models and in vivo, probably via low‐density lipoprotein receptor‐related protein 1. 49 The promoter haplotypes of VN, rs2227720 and rs2227721 have been detected in Chinese patients and show reduced promoter activity. Genotype rs222772 is positively related to VN levels in plasma, and rs222772‐T allele carriers are at high risk of vascular diseases like coronary atherosclerotic heart diseases and deep venous thrombosis. 50 As a cofactor of PAI‐1, the level and genotype of VN in LV patients may provide clues to its pathogenesis based on previous research on PAI‐1 in LV.

4.2. Glycosylation pattern of PAI‐1

Glycosylation refers to the process of forming glycosidic bonds between amino acid termini and glycosyl molecules. Protein modification and regulation of biological function can be completed by protein glycosylation. As a single‐chain glycoprotein, PAI‐1 has three potential N‐terminal glycosylation sites, and its glycosylation patterns tend to be heterogeneous in humans. 51 A previous study showed that the glycosylated human PAI‐1 structure may influence its stability. Because wild‐type PAI‐1 is thermally unstable, researchers have constructed a stabilised PAI‐1 variant by site‐directed mutagenesis based on stabilising mutations previously investigated, and they have compared the functional stability between nonglycosylated and the glycosylated stabilised variant PAI‐1. The results showed that the half‐life of glycosylated PAI‐1 in the stabilised form was approximately 8‐fold lower when compared with that of nonglycosylated stabilised variant PAI‐1. 52 Serrano et al provided evidence showing the higher inhibitory activity of glycosylated PAI‐1 when compared with that of the nonglycosylated PAI‐1. Glycosylated PAI‐1 was estimated to be 2.3‐fold more active against t‐PA and 10‐fold more active against u‐PA when compared with that of nonglycosylated PAI‐1 in insulin‐resistant rats. 53 Additionally, the highly glycosylated PAI‐1 and enhanced stability is associated with an increased risk of cardiovascular diseases under insulin‐resistant conditions. 53 Although elevated levels and an enhanced stability of PAI‐1 have been detected in LV patients, glycosylation pattern analysis of PAI‐1 has not been carried out in LV patients. Identifying differences in glycosylated PAI‐1 levels should help explain PAI‐1 abnormalities in LV.

4.3. Regulation of noncoding RNA

Most noncoding RNAs are so‐called functional RNAs that do not encode proteins but regulate biological functions by suppressing mRNA translation or promoting mRNA degradation. According to their molecule length and three‐dimensional structure, noncoding RNAs can be classified into microRNA (miR), circularRNA, and long noncoding RNA. 54 Both miR‐421 and miR‐30c are associated with PAI‐1 expression in human umbilical vein endothelial cells. A reduction of miR‐421 expression was demonstrated in venous thrombosis patients with low PAI‐1 levels rather than high PAI‐1 levels. 55 However, variability in the levels of plasma miR‐421 and miR‐30c was more likely to appear in the group of venous thrombosis patients with high levels of PAI‐1. 55 The correlation observed between circulating miR‐30c levels decreasing and PAI‐1 and VN levels increasing indicated that miR‐30c is a suitable biomarker for type 2 diabetes mellitus patients complicated with coronary heart disease through regulating the PAI‐1/VN interaction and VN, which was revealed in plasma and vascular smooth‐muscle cell models. 56 LV belongs to a thrombo‐occlusive vasculopathy of cutaneous small blood vessels and noncoding RNA targeting the expression of PAI‐1 and VN like miR‐421 and miR‐30c should also be examined in LV patients in an effort to understand the pathogenesis of LV.

5. CONCLUSION

In conclusion, as an essential component of many physiological processes and pathophysiological mechanisms, PAI‐1 participates in the pathogenesis of various diseases, including LV. By examining the function of PAI‐1 in thrombosis, cell adhesion and migration, angiogenesis and inflammation, we have provided the potential etiological role of PAI‐1 in the pathogenesis of LV. Further research aimed at unravelling the specific pathogenesis of PAI‐1 in LV should provide new insights to aid the development of therapeutics against LV.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

Gao Y, Jin H. Plasminogen activator inhibitor‐1: a potential etiological role in livedoid vasculopathy. Int Wound J. 2020;17:1902–1908. 10.1111/iwj.13480

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