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In recent years, cardiovascular disease has become the leading cause of disability and death among both urban and rural residents in China, driven largely by aging, diabetes, hypertension, hyperlipidemia, obesity, and smoking. However, vascular endothelial injury is also ubiquitous in atherosclerosis, hypertension, diabetic vascular complications, and several cardiovascular and cerebrovascular diseases. Endothelial cells (ECs) are important components of blood vessels, as they are arranged in a single vertical layer and are common targets in the development of cardiovascular disease. They not only form a barrier against allogenic material but also possess endocrine and immunological competence. Furthermore, they play an important role in vascular homeostasis, including by participating in vasoconstriction and vasodilation to control blood pressure, coagulation, atherosclerosis, and angiogenesis. Missing or dysfunctional ECs will expose damaged blood vessels to a variety of pathogenic factors so that the endogenous and extrinsic coagulation pathway is activated, and local thrombosis produces vessel stenosis or occlusion. At the same time, various inflammatory dielectrics, cytokines, and chemokines are produced around the damaged vessels. Under the stimulation of these factors, smooth muscle cells proliferate, leading to endothelial hyperplasia and complications of hemadostenosis which can endanger the patient's life.
However, it is unclear which key factors or links among them trigger endothelial injury and repair. Therefore, several studies have explored the characteristics and mechanisms of endothelial injury, as well as investigating the roles of the harmful or beneficial substances secreted by a damaged endothelium. The current research on endothelial injury chiefly focuses on inflammatory reactions, physical stimulations, chemical poisons, concurrency of related diseases, and molecular changes. On the other hand, ECs also possess the ability to proliferate and repair themselves. A variety of restorative cells, changes to cytokines and molecules, chemical drugs, certain RNAs, regulation of blood pressure, and physical fitness training can be beneficial to endothelial wound repair. The research progress in both endothelial injury and repair is described below.
The diagrammatic drawing in regard to the injury and repair in the common status of endothelial lining. →: Promote; (-): Inhibition. EC: Endothelial cells; EPCs: Endothelial progenitor cells; EMS: Electric muscle stimulation; HSCs: Hematopoietic stem cells; ECFCs: Endothelial colony forming cells; EOCs: Early outgrowth cells; NO: Nitric oxide; hAECs: Human amniotic epithelial cells; ADSCs: Adipose-derived stem cells; Tang: Angiogenic T cells; HBMP–2: Human bone morphogenic protein-2; MSCs: Mesenchymal stromal cells; eNOS: Endothelial nitric oxide synthase; apoA-I: Apolipoprotein A-I; HO-1: Heme oxygenase-1; ZFP580: Zinc finger transcription factor; H2O2: Hydrogen peroxide; IL-8: Interleukin-6; TNF: Tumor necrosis factor; sCD40L: Soluble CD40 ligand; MCP-1: Monocyte chemoattractant protein-1; IL-6: Interleukin-6; ZnO: Zinc oxide; VEGFR2: Vascular endothelial growth factor receptor 2; CXCR4: CXC chemokine receptor 4; s-ICAM1: Soluble intercellular adhesion molecule 1; ROS: Reactive oxygen species; NADPH: Nicotinamide adenine dinucleotide phosphate; MnSOD: Manganese superoxide dismutase.
Protective Factors Related to Endothelial Repair
Endothelial progenitor cells
Since the initial discovery of endothelial progenitor cells (EPCs), researchers have made meaningful progress toward a strict functional description and a better interpretation of EPCs, which have been successfully used to stimulate vascular repair and angiogenesis in some experimental settings. Moreover, EPC-containing products (such as bone marrow or mobilized peripheral blood), which are a kind of human autologous cell therapies, have proven to be viable and valid options in the treatment of atherosclerotic disease. Furthermore, significantly higher levels of circulating CD34+ KDR+ cells are consistent with the number of EPCs improving endothelial repair. Thus, CD34+ KDR+ cells may become the key to successful therapies that require targeting several parallel mechanisms for a long time. They are also integral to novel molecular strategies and translational developments of cerebrovascular treatments in patients with type 2 diabetes mellitus. Since circulating CD34+ cells have been reported to be beneficial to endothelial repair (and thus to vascular repair and the development of atherosclerosis), this factor could be a biomarker for the activity of the vicious between endothelial damage and hypertension common in elderly men.
What's more, external electric muscle stimulation (EMS) reduced symptoms of vascular lesions induced by diabetic neuropathy and decreased diastolic blood pressure. A single EMS remedy fortified the function of certain molecules which can mediate differentiation and attachment on the surface of hematopoietic stem cells (HSCs) during blood circulation. A new assumption is that the EMS-induced increase in surface attachment molecules on HSCs allows the HSCs to leave blood circulation and that the EMS remedy boosts the effect of EPCs and HSCs. However, the downregulation of Notch1 also enhanced the proliferation, differentiation, migration, and adhesion of EPCs, along with the capacity to form human vein ECs. In spite of a number of studies revealing correlations between circulating EPC phenotypes and patient traits and prognosis, the pathophysiological effect of circulating EPC concentrations is still unclear.
Other correlative cells
Endothelial repair can be considered from the cell's perspective as a result of the lesions originating from ECs. Recent evidence illuminates the presence of two EPC subtypes: endothelial colony-forming cells (ECFCs) and early outgrowth cells (EOCs). Their different morphological and phenotypic characteristics, and more importantly, the release of the antiaggregating agents prostacyclin 2 and nitric oxide (NO) in each EPC subtype, are implicated in their respective roles in endothelial function and thus may be linked to the better efficiency of ECFCs in inhibiting endothelial injury during endothelial regeneration. First, in vascular regenerative medicine, human amniotic epithelial cells (hAECs) are a promising means for endothelial repair. Vácz et al. concluded that, without immunosuppression, hAECs were capable of intruding into the vascular wall but were incapable of enhancing vascular condition. She emphasized that this process can achieve the aim of morphological implantation and cannot gain the functional benefits, highlighting the necessity to research other theories of endothelial repair. In addition, Hasdemir et al. proposed that, after a radiation injury, adipose-derived stem cells have an underlying capacity for strengthening hemokinesis, which might be accompanied with endothelial repair and needs further study. More recently, angiogenic T cells (Tang) have been recently discovered to cooperate with EPCs in endothelial repair. The main aim of Rodríguez-Carrio et al.'s research was to analyze the Tang and EPC numbers in relation to traditional cerebrovascular risk factors. The increase of Tang has a protective effect on the endothelium. At present, cell replacement therapy is an idealized and novel strategy for endothelial injury, but there are also numerous obstacles and difficulties such as immunological rejection, ethical issues involving embryos, and a limited number of cells.
Cytokines or molecules
From a microscopic perspective, molecular expression plays an important role in endothelial repair. In the case of irradiation in rats, severe endothelial injury was produced, but treatment with human bone morphogenic protein-2 (HBMP-2) combined with mesenchymal stromal cells (MSCs) accelerated repair. By regulating hypoxia-inducible factor-1 α expression (which influences endothelial formation and recovery), and by upregulating the expression of the endothelial NO synthase (eNOS) pathway, HBMP-2 exerts its effect. These findings suggest that novel methods for adding molecules or cytokines to MSCs should be evaluated for remedying chronic radiation-induced damage to the endothelium.
Apolipoprotein A-I (apoA-I) mimetic peptide has many antiatherogenic features which improve the impaired endothelial proliferation and migration resulting from oxidized low-density lipoprotein, by reducing EC apoptosis and upregulating the expression of heme oxygenase-1 (HO-1) and eNOS. Moreover, the antioxidation, proproliferation, and promigration abilities of apoA-I were cut down by the inhibitors of both eNOS and HO-1. Next, increasing high-density lipoprotein (HDL) concentrations by inhibiting the cholesteryl ester transfer protein reduces intimal thickening and regenerates functional endothelia in damaged aortas in a scavenger receptor-B1-dependent and phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt-dependent manner. In summary, the results suggest that apoA-I and cholesteryl ester transfer protein inhibition might be commendable candidates for the protection of ECs and the prevention of atherosclerotic disease.
Along similar lines, novel zinc finger transcription factor (ZFP580) facilitates not only the differentiation of EPCs into ECs by upregulating the availability of NO and the expression of eNOS but also endothelial formation. This may demonstrate a new theory of ZFP580 in EPC evolution and its meaningful value in the remedy of vascular damage. Adepu et al.'s research shows that early injury in transplanted kidneys causes repair stimulations, specifically tubular syndecan-1 expression for endothelial neogenesis. Syndecan-1 is a transmembrane heparan sulfate proteoglycan involved in regenerative growth and cellular adhesion. Increased serum syndecan-1 concentrations might be a repair factor relevant to endothelial function. Moreover, bone marrow-derived cellular therapies are a new and developing strategy to improve therapeutic endothelial neogenesis in atherosclerotic disease. Specifically, ixmyelocel-T is manufactured from a small sample of bone marrow aspirate, forming an expanded autologous multicellular therapy. Ledford et al. reported that ixmyelocel-T cooperates with ECs in a paracrine manner, leading to endothelial protection and angiogenesis. This result shows that ixmyelocel-T could be beneficial for improving endothelial repair in ischemic cardiovascular and cerebrovascular diseases. In a word, ixmyelocel-T treatment may offer a novel insight into remedial vasculogenesis in patient populations requiring an increased number of reborn cells.
Chemical drugs
Endothelial-protective chemical drugs, including lipid-lowering medicines, anti-human immunodeficiency virus (HIV) drugs, hypoglycemic drugs, hypotensor, and Vitamin D, play a role in endothelial repair mainly by treating concomitant diseases, which can achieve better results. First, in terms of lipid-lowering medicines, present clinical worries center on restraining the proliferation of smooth muscle cells by utilizing drug-eluting stents. It is unfortunate that this approach can also suppress endothelial proliferation and prevent EC repair. However, Hussner's data offered enough proof and a theoretical basis for using atorvastatin in stents to avoid this dilemma. Furthermore, Li et al. researched the capacity of atorvastatin to guard ECFCs, a subtype of EPCs, and to demonstrate a potential protective effect from hydrogen peroxide (H2O2)-induced oxidative injury. Furthermore, Rosuvastatin improved re-endothelialization by regulation of EPCs, proposing that facilitating endothelial recovery offers a fresh therapeutic strategy for vascular repair.
Second, one study demonstrates that anti-HIV drugs can promote the repair of impaired endothelia. Recovery of the serum concentration of EPCs was higher in darunavir-remedied individuals than in those remedied with rilpivirine, suggesting promising endothelial repair methods. Third, hypoglycemic medicine can effectively reduce blood glucose concentrations, weaken the damage of high sugar on ECs, and form an endothelial protection mechanism. Metformin has an underlying endothelium-protective function through promoting the level of EPCs and EC and markedly affecting hypoglycemic function. Similarly, irisin was proven to promote endothelial regeneration in diabetic mice that received EPC transplants after vascular damage. Fourth, store-operated calcium entry (SOCE), a major mode of extracellular calcium entry, plays a part in all kinds of cell activities. SOCE inhibition can have a favorable influence on EPCs after exposure to oxidative stress caused by oxidizing agents and may provide an underlying method to compete with endothelial damage. Fifth, in Reynolds et al.'s experimental research, calcitriol promoted endothelial repair in individuals with systemic lupus erythematosus (SLE). The results demonstrate that Vitamin D could be a new treatment to decrease atherosclerotic disease and protect the ECs from damage. Recently, there have been some new reports that the prostacyclin has a certain role in the repair of endothelial injury, but it is not very clear and needs further study.
Other approaches to endothelial repair
The repair of the endothelium involves a variety of aspects including certain RNAs, regulation of blood pressure, physical fitness training, number of blood platelets, and physical stimulation. Although the whole network of microRNAs (miRNAs) involved in the process is still largely unknown, present evidence shows that therapeutic replacement of 23 miRNAs, miR-126-5p, miR-155, and other miRNAs, which help maintain the vascular homeostasis of EPCs, may restore endothelial health and reduce atherosclerosis. Furthermore, hypertension might indicate an insufficient ability for adequate vascular maintenance, so lowering blood pressure is a protective strategy and a therapeutic prospect for repairing damaged vascular ECs. Next, the number and activity of ECs in men and increased CD34+ cells in women are enhanced through exercise. Finally, as to physical stimulation, external EMS, shear stress, and hypoxia are vital nonpharmacologic methods to improve the activity of EPCs. These findings provide novel nonpharmacologic therapeutic methods for hypertension-interrelated endothelial neogenesis.