Endothelial progenitor cell therapy for the treatment of coronary disease, acute MI, and pulmonary arterial hypertension: current perspectives.

Since their identification in 1997, bone marrow derived endothelial progenitor cells (EPCs) have been studied for their role in the endogenous maintenance and repair of endothelium and their potential regenerative capacity beyond the endothelium. In particular, EPCs have been tested in cell therapy approaches with the aim of developing novel therapies for conditions currently lacking effective treatment options. In this review, we discuss the scientific background and clinical experience using EPC delivery or mobilization for the treatment of post-angioplasty restenosis, acute myocardial infarction and pulmonary arterial hypertension. Although these approaches are safe, efficacy has yet to be proven in large randomized clinical trials. Unfortunately, the biology of EPCs is still poorly understood. The success of future clinical trials depends on a better understanding of EPC biology and intelligent design.     

Cell-Based Therapies for Diabetic Retinopathy

Autologous endothelial progenitor cell (EPC) populations represent a novel treatment for therapeutic revascularization and vascular repair for diabetic patients with complications including diabetic retinopathy. Current therapies are applicable to late-stage disease and carry significant side effects, whereas cell-based therapy may provide an alternative by repairing areas of vasodegeneration and reversing ischemia. However, EPCs from diabetic patients with vascular complications are dysfunctional. Moreover, the diabetic environment poses its own challenges and complicates the use of autologous EPCs. Before EPCs become the ideal “cell therapy,” the optimal EPC must be determined, any functional dysfunction must be corrected prior to use, and the diabetic milieu will require modification to accept the EPCs. This review describes the rationale for harnessing the vascular reparative properties of EPCs with emphasis on the molecular and phenotypic nature of healthy EPCs, how diabetes alters them, and novel strategies to improve dysfunctional EPCs.     

Endothelial progenitor cells: a promising therapeutic alternative for cardiovascular disease

The integrity and functional activity of the endothelial monolayer play a critical role in preventing atherosclerotic disease progression. Endothelial cell (EC) damage by atherosclerosis risk factors can result in EC apoptosis with loss of the integrity of the endothelium. Thus, approaches to repair the injured vessels with the goal of regenerating ECs have been tested in preclinical experimental models and in clinical studies. Indeed, endothelial progenitor cells (EPCs) originating from the bone marrow have been shown to incorporate into sites of neovascularization and home to sites of endothelial denudation. These cells may provide an endogenous repair mechanism to counteract ongoing risk factor-induced endothelial injury and to replace dysfunctional endothelium. Risk factors for coronary artery disease, such as age, smoking, hypertension, hyperlipidemia, and diabetes, however, reduce the number and functional activity of circulating EPCs, potentially restricting the therapeutic prospective of progenitor cells and limiting the regenerative capacity. Furthermore, the impairment of EPCs by risk factors may contribute to atherogenesis and atherosclerotic disease progression. The article reviews the role of EPCs in atherogenesis and in predicting cardiovascular outcomes, and highlights the potential challenges in developing therapeutic strategies aiming to interfere with the balance of injury and repair mechanisms.     

Does drug therapy reverse endothelial progenitor cell dysfunction in diabetes?

Endothelial progenitor cells (EPCs) are vital for the maintenance and repair of the endothelium. Decreased EPC number and function have been associated with increased cardiovascular (CVD) risk. Patients with diabetes have decreased number of circulating EPCs and decreased EPC function. This may account for some of the increased CVD risk seen in patients with diabetes that is not explained by traditional risk factors such as glycemic control, dyslipidemia and hypertension. Recent studies seem to indicate that drugs commonly used in diabetes patients such as metformin, thiazolidinediones, GLP-1 agonists, DPP-4 inhibitors, insulin, statins and ACE inhibitors may increase EPC number and improve EPC function. The mechanisms by which these drugs modulate EPC function may involve reduction in inflammation, oxidative stress and insulin resistance as well as an increase in nitric oxide (NO) bioavailability. This review will discuss the evidence in the literature regarding the above mentioned topics.     

Endothelial progenitor cells in cardiovascular disorders

The important role of the vascular endothelium in cardiovascular health is increasingly recognized. However, mature endothelial cells possess limited regenerative capacity. There is therefore much interest in circulating endothelial progenitor cells (EPCs) among the scientific community, especially into their purported role in maintenance of endothelial integrity and function, as well as postnatal neovascularization. It has been suggested that these cells might not only be responsible for the continuous recovery of the endothelium after injury/damage, but also might take part in angiogenesis, giving the hope of new treatment opportunities. Indeed, there is accumulating evidence showing reduced availability and impaired EPC function in the presence of both cardiovascular disease and associated comorbid risk factors. Thus, many studies into the potential for use of EPCs in the clinical setting are being undertaken. The goal of this review article is to provide an overview of data relevant to the clinical role of EPCs and perspectives for treatment of cardiovascular disorders.     

Endothelial progenitor cells in cardiovascular disorders.

The important role of the vascular endothelium in cardiovascular health is increasingly recognized. However, mature endothelial cells possess limited regenerative capacity. There is therefore much interest in circulating endothelial progenitor cells (EPCs) among the scientific community, especially into their purported role in maintenance of endothelial integrity and function, as well as postnatal neovascularization. It has been suggested that these cells might not only be responsible for the continuous recovery of the endothelium after injury/damage, but also might take part in angiogenesis, giving the hope of new treatment opportunities. Indeed, there is accumulating evidence showing reduced availability and impaired EPC function in the presence of both cardiovascular disease and associated comorbid risk factors. Thus, many studies into the potential for use of EPCs in the clinical setting are being undertaken. The goal of this review article is to provide an overview of data relevant to the clinical role of EPCs and perspectives for treatment of cardiovascular disorders.     

Role of inflammation and oxidative stress in endothelial progenitor cell function and mobilization: therapeutic implications for cardiovascular diseases

Endothelial progenitor cells (EPCs) are mobilized from the bone marrow into the peripheral circulation, home to sites of injury, and incorporate into foci of neovascularization, thereby improving blood flow and tissue recovery. Patients with cardiovascular diseases, including coronary artery disease, heart failure, hypertension, and diabetes, have been shown to exhibit reduced number and functional capacity of EPCs. Considerable evidence indicates that EPCs constitute an important endogenous system to maintain endothelial integrity and vascular homeostasis, while reduced number of EPCs has recently been shown to predict future cardiovascular events. Thus, enhancement of EPCs could be of potential benefit for individuals with cardiovascular diseases. The interplay between inflammation and oxidative stress is involved in the initiation, progression, and complications of cardiovascular diseases. Emerging evidence from in vitro and clinical studies suggests that inflammatory and oxidative changes influence EPC mobilization. Drugs with anti-inflammatory and antioxidant properties, currently administered to patients with cardiovascular diseases, such as statins, have been demonstrated to exert beneficial effects on EPC biology. A better understanding of the inflammatory and oxidative mechanisms leading to the numerical and functional impairment of EPCs would provide additional insight into the pathogenesis of cardiovascular disease and create novel therapeutic targets.     

Endothelial progenitor cells: mobilization,differentiation, and homing

Postnatal bone marrow contains a subtype of progenitor cells that have the capacity to migrate to the peripheral circulation and to differentiate into mature endothelial cells. Therefore, these cells have been termed endothelial progenitor cells (EPCs). The isolation of EPCs by adherence culture or magnetic microbeads has been described. In general, EPCs are characterized by the expression of 3 markers, CD133, CD34, and the vascular endothelial growth factor receptor-2. During differentiation, EPCs obviously lose CD133 and start to express CD31, vascular endothelial cadherin, and von Willebrand factor. EPCs seem to participate in endothelial repair and neovascularization of ischemic organs. Clinical studies using EPCs for neovascularization have just been started; however, the mechanisms stimulating or inhibiting the differentiation of EPC in vivo and the signals causing their migration and homing to sites of injured endothelium or extravascular tissue are largely unknown at present. Thus, future studies will help to explore areas of potential basic research and clinical application of EPCs.     

Spotlight on endothelial progenitor cell inhibitors: short review

Endothelial progenitor cells (EPCs) are bone-marrow-derived cells that enter the systemic circulation to replace defective or injured mature endothelial cells. EPCs also contribute to neovascularization and limit the progression of atherosclerosis. Patients with reduced EPC levels or dysfunctional EPCs are at increased risk for coronary artery disease. Drug-mediated improvement of the mobilization, differentiation, function and homing of EPCs to sites of ischemia or injured endothelium may therefore be a promising novel therapeutic approach for various cardiovascular diseases. On the other hand, endogenous inhibitors of EPCs could also be valuable drug targets. The identification of EPC inhibitors and the development of novel drugs that can efficiently regulate production or elimination of these molecules may also be a promising approach for the future treatment of atherosclerosis. In the present review we summarize potential endogenous and exogenous inhibitors of EPCs, such as oxidized low-density lipoproteins, angiotensin II, glucose, cigarette smoke and others. Whenever possible, we also describe the underlying molecular events. Drug-induced mobilization and improvement of EPC function, as well as reduction of EPC inhibitors, is likely to enhance endothelial function and reduce atherosclerotic processes.     

Technical notes on endothelial progenitor cells: ways to escape from the knowledge plateau

In the last 10 years an increasing interest has been devoted to the study of endothelial progenitor cells (EPCs), a subtype of immature cells involved in endothelial repair and neoangiogenesis. EPCs have been discovered as a novel integrated part of the cardiovascular system, which plays a comprehensive role in tissue homeostasis. Consistently, alterations and/or reduction of the circulating EPC pool have been associated with different manifestations of cardiovascular disorders and atherosclerosis. This is why, the extent of the EPC pool is now considered a mirror of vascular health, while EPC reduction has become a surrogate biomarker of cardiovascular risk and of the ongoing vascular damage. Unfortunately, the methods used to study EPCs still lack standardization, and this is significantly decelerating progress in the field. In this review, we focus on some aspects related to the two methods used to assess circulating EPCs: flow cytometry and cell culture. We uncover the many traps hidden in the choice of the right protocol, and suggest the best solutions on the basis of evidence and background theories.     

Influence of cardiovascular risk factors on endothelial progenitor cells: limitations for therapy?

The ideal way to prevent and cure atherosclerosis and the subsequent end organ damage is to restore and rejuvenate the dysfunctional vasculature and the damaged organs. Various studies have underlined the important role of bone marrow-derived endothelial progenitor cells (EPCs) in vasculogenesis and angiogenesis of ischemic tissue, but only a few studies have concentrated on the role of EPCs in the prevention and therapy of atherosclerosis. Extended endothelial cell damage by cardiovascular risk factors can result in endothelial cell apoptosis with loss of the integrity of the endothelium. The consequences are an increased vascular permeability of the endothelium followed by facilitated migration of monocytes and vascular smooth muscle cell proliferation, resulting in the premature manifestation of an atherosclerotic lesion. A growing body of evidence suggests that circulating EPCs play an important role in endothelial cell regeneration. Systemic transfusion or intrinsic mobilization of EPCs enhances the restoration of the endothelium after focal endothelial denudation, resulting in a diminished neointima formation. In mice with atherosclerotic lesions, bone-marrow-derived stem cells are able to reduce atherosclerotic plaque size. However, various studies have demonstrated that in humans, cardiovascular risk factors impair number and function of EPCs, potentially restricting the therapeutic potential of progenitor cells. The current review focuses on the role of cardiovascular risk factors on endothelial cell apoptosis and EPCs with its pathophysiological consequences for atherogenesis and a regenerative therapy approach and will highlight the role of EPCs as a marker for cardiovascular mortality and morbidity.     

Adenosine receptor-mediated adhesion of endothelial progenitors to cardiac microvascular endothelial cells

Intracoronary delivery of endothelial progenitor cells (EPCs) is an emerging concept for the treatment of cardiovascular disease. Enhancement of EPC adhesion to vascular endothelium could improve cell retention within targeted organs. Because extracellular adenosine is elevated at sites of ischemia and stimulates neovascularization, we examined the potential role of adenosine in augmenting EPC retention to cardiac microvascular endothelium. Stimulation of adenosine receptors in murine embryonic EPCs (eEPCs) and cardiac endothelial cells (cECs) rapidly, within minutes, increased eEPC adhesion to cECs under static and flow conditions. Similarly, adhesion of human adult culture-expanded EPCs to human cECs was increased by stimulation of adenosine receptors. Furthermore, adenosine increased eEPC retention in isolated mouse hearts perfused with eEPCs. We determined that eEPCs and cECs preferentially express functional A1 and A2B adenosine receptor subtypes, respectively, and that both subtypes are involved in the regulation of eEPC adhesion to cECs. We documented that the interaction between P-selectin and its ligand (P-selectin glycoprotein ligand-1) plays a role in adenosine-dependent eEPC adhesion to cECs and that stimulation of adenosine receptors in cECs induces rapid cell surface expression of P-selectin. Our results suggest a role for adenosine in vasculogenesis and its potential use to stimulate engraftment in cell-based therapies.     

Endothelial Dysfunction as an Early Sign of Atherosclerosis

The endothelium, the monolayer covering the inner surface of blood vessels, plays a pivotal role in the regulation of vascular tone and structure, as well as vascular inflammation and thrombosis, i.e., of key events of the atherosclerotic disease process and its clinical complications, such as myocardial infarction and stroke. In particular a reduced endothelial availability of nitric oxide (NO), in part due to increased vascular oxidant stress, has been shown to promote a pro-inflammatory and prothrombotic phenotype of the endothelium. More recently, it has been observed that cardiovascular risk factors reduce the number and impair the function of circulating bone marrow-derived endothelial progenitor cells (EPCs), thereby impairing the endogenous endothelial repair capacity.Importantly, endothelial dysfunction has been identified as a common link of all cardiovascular risk factors. Numerous clinical studies have further demonstrated a close association of the degree of endothelial dysfunction with the risk of future cardiovascular events. Whether endothelial dysfunction can improve cardiovascular risk prediction on top of a careful evaluation of classic cardiovascular risk factors is currently prospectively analyzed in several studies, i.e., in the PREVENT-it study. Furthermore, novel easier to use methods to assess endothelial function are currently explored, i.e., the Endo-PAT system, for their potential in improving cardiovascular risk prediction.At present, assessment of endothelial function and EPCs are highly valuable research tools to improve our understanding of mechanisms of vascular disease and to determine the impact of novel therapeutic approaches on vascular function. Before endothelial function measurements can, however, be recommended in clinical practice for cardiovascular risk assessment, the results of ongoing prospective studies assessing the additive value of these measurements for cardiovascular risk prediction should be awaited.     

Interferon-alpha promotes abnormal vasculogenesis in lupus: a potential pathway for premature atherosclerosis

Individuals with systemic lupus erythematosus (SLE) have a striking increase in premature atherosclerosis of unclear etiology. Accelerated endothelial cell apoptosis occurs in SLE and correlates with endothelial dysfunction. Endothelial progenitor cells (EPCs) and myelomonocytic circulating angiogenic cells (CACs) are crucial in blood vessel repair after vascular damage, and decreased levels or abnormal function of EPCs/CACs are established atherosclerosis risk factors. We investigated if vascular repair is impaired in SLE. We report that SLE patients display abnormal phenotype and function of EPCs/CACs. These abnormalities are characterized by significant decreases in the number of circulating EPCs (310 +/- 50 EPCs/mL of blood in SLE versus 639 +/- 102 in controls) and significant impairments in the capacity of EPCs/CACs to differentiate into mature ECs and synthesize adequate levels of the proangiogenic molecules vascular endothelial growth factor (VEGF) and hepatic growth factor (HGF). These abnormalities are triggered by interferon-alpha (IFN-alpha), which induces EPC and CAC apoptosis and skews myeloid cells toward nonangiogenic phenotypes. Lupus EPCs/CACs have increased IFN-alpha expression and their supernatants promote higher induction of IFN-inducible genes. Importantly, neutralization of IFN pathways restores a normal EPC/CAC phenotype in lupus. SLE is characterized by an imbalance between endothelial cell damage and repair triggered by type I IFNs, which might promote accelerated atherosclerosis.     

Thiazolidinediones-improving endothelial function and potential long-term benefits on cardiovascular disease in subjects with type 2 diabetes

Endothelial dysfunction, which leads to impaired vasodilation, is an early event in the development of atherosclerosis. A number of mechanisms involving, for example, cell adhesion molecules, chemokines, and cytokines, contribute to this inflammatory disease, and insulin resistance plays a cardinal role in accelerating these processes. Hyperglycemia and other metabolic abnormalities that are commonly associated with insulin resistance also contribute to impaired endothelial function. In addition, the important role of the endothelium in damage repair following a cardiovascular event is emerging. The combination of proatherogenic factors in patients with type 2 diabetes results in blunted endothelial function and an increased risk of cardiovascular disease. Insulin-sensitizing agents such as thiazolidinediones have demonstrated a number of clinical benefits, including anti-inflammatory and antithrombotic properties, which may impact on the course of atherosclerosis. Recent studies have demonstrated that thiazolidinediones improve endothelial function in subjects with and without type 2 diabetes.     

Endothelial progenitor cells:Exploring the pleiotropic effects of statins

Statins have become a cornerstone of risk modification for ischaemic heart disease patients. A number of studies have shown that they are effective and safe. However studies have observed an early benefit in terms of a reduction in recurrent infarct and or death after a myocardial infarction,prior to any significant change in lipid profile. Therefore,pleiotropic mechanisms,other than lowering lipid profile alone,must account for this effect. One such proposed pleiotropic mechanism is the ability of statins to augment both number and function of endothelial progenitor cells. The ability to augment repair and maintenance of a functioning endothelium may have profound beneficial effect on vascular repair and potentially a positive impact on clinical outcomes in patients with cardiovascular disease. The following literature review will discuss issues surrounding endothelial progenitor cell(EPC) identification,role in vascular repair,factors affecting EPC numbers,the role of statins in current medical practice and their effects on EPC number.     

Therapeutic potential of endothelial progenitor cells in cardiovascular diseases

Endothelial dysfunction and cell loss are prominent features in cardiovascular disease. Endothelial progenitor cells (EPCs) originating from the bone marrow play a significant role in neovascularization of ischemic tissues and in re-endothelialization of injured blood vessels. Several studies have shown the therapeutic potential of EPC transplantation in rescue of tissue ischemia and in repair of blood vessels and bioengineering of prosthetic grafts. Recent small-scale trials have provided preliminary evidence of feasibility, safety, and efficacy in patients with myocardial and critical limb ischemia. However, several studies have shown that age and cardiovascular disease risk factors reduce the availability of circulating EPCs (CEPCs) and impair their function to varying degrees. In addition, the relative scarcity of CEPCs limits the ability to expand these cells in sufficient numbers for some therapeutic applications. Priority must be given to the development of strategies to enhance the number and improve the function of CEPCs. Furthermore, alternative sources of EPC such as chord blood need to be explored. Strategies for improvement of cell adhesion, survival, and prevention of cell senescence are also essential to ensure therapeutic viability. Genetic engineering of EPCs may be a useful approach to developing these cells into efficient therapeutic tools. In the clinical arena there is pressing need to standardize the protocols for isolation, culture, and therapeutic application of EPC. Large-scale multi-center randomized trials are required to evaluate the long-term safety and efficacy of EPC therapy. Despite these hurdles, the outlook for EPC-based therapy for cardiovascular disease is promising.     

Vascular repair by endothelial progenitor cells

Accumulating evidence indicates the impact of endothelial progenitor cells (EPCs) in vascular repair. In patients, the number of EPCs is negatively correlated with the severity of atherosclerosis. In various animal models, transplantation of bone marrow-derived progenitor cells could sufficiently rescue organ function and enhance vascular repair and tissue regeneration. Increase in the number of circulating progenitors, induced by cell transfusion or enhanced mobilization, can also enhance restoration and integrity of the endothelial lining, suppress neointimal formation, and increase blood flow to ischaemic sites. However, the beneficial outcome of EPC infusion very much depends on the growth and differentiation factors within the tissue, cell-to-cell interactions, and the degree of injury. As highlighted by several studies, EPCs derive from different sources including bone marrow and non-bone marrow organs such as the spleen, the functional repair properties of which may vary with the maturation state of the cell. Thus, understanding the molecular mechanisms involved in EPC-repairing processes is essential. In the present review we focus on the role of EPCs in vascular diseases, and we provide an update on the mechanisms of EPC mobilization, homing, and differentiation.     

Adult vascular progenitor cells and tissue regeneration in metabolic syndrome

Adult vascular progenitor cells (for example endothelial progenitor cells, EPC) have been studied for their contribution to vascular repair and angiogenesis. These cells can differentiate from bone marrow cells as well as circulating cells carrying hematopoetic stem cell markers. In vivo, they take part in vasculogenesis in different animal models of limb ischemia, myocardial infarction and wound healing. In metabolic disease, the outgrowth and function of EPC in vitro is defective and numbers of EPC correlate with classical risk factors of cardiovascular disease suggesting a role of EPC in the development of vascular complications. Pilot studies for the treatment of myocardial infarction and limb ischemia with autologous bone marrow showed a distinct therapeutic benefit that is presumably mediated by vasculogenesis in damaged tissues. However, little is known about the nature of EPC and their capability to differentiate into functional cells for tissue regeneration. In this article, we review and discuss the hitherto identified physiological function of EPC, the mechanisms leading to dysfunction of these cells and potential therapeutic applications in patients with metabolic syndrome or diabetes mellitus and vascular complications.     

Endothelial progenitor cells in the natural history of atherosclerosis

Atherosclerotic diseases are responsible for a significant part of morbidity and mortality in western countries. According to the classical views, atherosclerotic lesions develop as the result of an inflammatory process initiated by endothelial damage. The discovery that bone marrow-derived cells participate in endothelial repair and new vessel growth has changed the pathogenetic models of cardiovascular disease. These cells, termed endothelial progenitor cells (EPCs), represent the endogenous endothelial regenerative capacity and the ability to form new collateral vessels. In this review we describe how quantitative and qualitative alterations of EPCs have a significant role in virtually all stages of the atherosclerotic process and in the clinical manifestations of the diseases: starting from the impact of risk factors on EPCs, through the mechanisms that link EPC reduction/dysfunction to plaque formation, and finally to the clinical syndromes. An attempt to diverge our attention from the vessel wall to the bloodstream reveals a central role of EPCs in atherogenesis.