Current Vascular Pharmacology - Volume 10, Issue 3, 2012

Shortly after its birth, stem cell therapy became a powerhouse in health research and continues to hold great expectations for reversing or treating various diseases. Independent clinical trials showed improvements in patients with ischemic myocardium, peripheral arterial disease or stroke after transplantation with marrow- or peripheral blood-derived angiogenic adult cells, arguably some of the safest stem cells for clinical application [1-4]. Despite these promising results, larger randomized trials are needed to confirm the findings, and improvements in the magnitude of the revascularization response to treatment are still desired. The results seen in the clinic are in contrast to the much more encouraging results that were initially seen in animal models. Now, after these initial bench-to-bedside investigations, researchers are making a return to the bench in order to better assess and improve upon the methods of cell therapy. It was initially believed that transplanted stem cells would constitute newly developed vessels and that this was the mechanism by which neovascularization occurred. Later studies instead demonstrated that the main source of neovascularization was a paracrine signaling cascade, which is augmented and/or amplified by transplanted cells, and that the process of vascular regeneration is then largely maintained by the host's own endogenous cell populations [5, 6]. Performing similar in vivo work and “transplanting” acellular conditioned medium and observing similar functional effects further supports this mechanism [7, 8]. Essentially, transplantable cells act as pharmacological production factories, responding to their environment and producing desired cytokines to better aid the regenerative process. Based on this, stem cells may have the potential to reduce, complement, or replace the requirement for pharmacological treatment in vascular disease patients. However, several limitations exist that are restricting the success achieved by the application of cell therapy for vascular disease in the clinic [9, 10]. Firstly, transplanted cells exhibit poor persistence and viability. In theory, overcoming this hurdle would prolong the therapeutic production of “natural drugs”. Secondly, patients at risk, namely diabetics and those with ischemic heart disease, have endogenous stem cell populations that are greatly limited in their therapeutic potential. Reversing the dysfunction of cells from disease-state patients could improve cell therapy two-fold: autologous cells could be harvested and transplanted, and endogenous cells could be activated or stimulated to be more therapeutically effective in situ.....

Diabetes and pre-diabetes are major contributors to cardiovascular mortality and morbidity. Insulin resistance is a key pathophysiological determinant of the metabolic and vascular abnormalities noted in these disorders. Ineffective vascular repair is likely to be an important contributor to the development of endothelial dysfunction, and subsequently atherosclerosis, in patients with diabetes. Beyond the systemic effects of the insulin resistant phenotype, including factors such as dysglycaemia and inflammation, cellular insulin resistance is emerging as an important factor in diabetic vascular disease. Disordered signal transduction via the PI3-kinase/Akt and MAP-kinase cascades is a hallmark of cellular insulin resistance, and such changes have been linked with both endothelial dysfunction and impaired angiogenesis. In this review we highlight the importance of insulin resistance to vascular repair and regeneration, discuss important cross-talk between the intracellular signalling of insulin and key pro-angiogenic molecules, and link these concepts to common patterns of vascular disease.

Cell-based therapies are a novel approach for regeneration of microvasculature. We have shown that administration of CD34-positive cells, the rich cell fraction of endothelial progenitor cells, after stroke induces angiogenesis that results in enhanced endogenous neurogenesis and functional recovery in a murine model. Moreover, injury-induced neurogenesis occurs in the human brain following a stroke during the acute to sub-acute period. Based on these observations, clinical trials of cell therapies that aim to regenerate micro-circulation in the brain following a stroke are ongoing worldwide. This review summarizes the current basic research findings about the link between angiogenesis and neurogenesis in the post-stroke brain and introduces the ongoing clinical trials of cell-based therapies for patients that have suffered a stroke.

Since their initial discovery, endothelial progenitor cells (EPCs) have held tremendous promise for cell therapy for a variety of cardiovascular diseases including pulmonary hypertension. The clinical experience to date suggests that circulating or bone marrow mononuclear cells and EPCs can induce neovascularization, and enhance cardiac repair after myocardial function, as well as improvements in the hemodynamic and functional status of patients with idiopathic pulmonary arterial hypertension. Although these results are promising, the overall magnitude of the clinical benefits seen in these trials appear to be rather modest. Indeed, strong experimental evidence points towards a reduction in mobilization and impairment in function of EPCs in preclinical models and patients with cardiac disease or with cardiovascular risk factors such as advanced age, type I and II diabetes, hypercholesterolemia, coronary artery disease, as well as other conditions such as pulmonary hypertension. Genetic engineering of EPCs ex vivo, prior to transplantation, is a promising cell-enhancement strategy for restoring the angiogenic potential of autologous, patient-derived cells. This review provides an update of the experimental studies that have used gene-modified EPC therapy to treat ischemic cardiovascular disease and pulmonary hypertension.

Cardiovascular disease continues to be a major cause of death in the Western world and has been extending into areas previously seemingly immune to its effects. Catheter-based interventions and coronary artery bypass surgery have markedly improved cardiovascular health, but a number of patients with coronary artery disease cannot undergo repeated interventions or they receive an incomplete revascularization with standard revascularization methods, which has been associated with a poor clinical outcome. Despite early demonstration of improvement in myocardial perfusion and function with growth factor, gene therapy or cellular therapies, clinical studies have found little if any real benefit. The discordance between positive pre-clinical studies and essentially negative clinical trials may in part be explained by a number of factors including abnormal vascular signaling, oxidative stress, a hostile local myocardial environment and technical issues related to the administration of these therapies. Patients with end-stage coronary disease are vastly different from the young, healthy animals that are generally used for pre-clinical testing. The presence of diabetes, hypercholesterolemia, and other conditions associated with endothelial dysfunction and coronary disease and altered vascular signaling can significantly limit the effectiveness of growth factors on the development of collateral vessels. This paper summarizes the results of regenerative therapies for the treatment of coronary disease and discusses the reasons why growth factor protein, gene therapies and cellular therapies have not been overall successful to date.

Bone marrow (BM) holds a pool of stem and progenitor cells whose role is not limited to hematopoiesis. Indeed, growing evidences showed that BM-derived progenitors could contribute to various extents to cardiovascular homeostasis. Notably, diabetic patients experience an intrinsic defect of the progenitor pool, whereas some recent works point directly to an intrinsic defect of the BM, resulting in defective mobilization and impaired functions of progenitors. These defects could have important pathophysiological roles in the development of diabetic complications. An integrated approach, which enhances mobilization of progenitors and improves their functions, could represent a novel method to improve cardiovascular repair by endogenous progenitors. Furthermore, potential clinical trials of cell therapy would gain benefit from stratagems that enhance the number and functions of progenitors prior to transplantation. In this review we discuss the strategies to stimulate the mobilization of progenitors in diabetes and the protocols to improve their functions.

Due to the very limited ability of cardiac tissue to self-regenerate, the replacement of damaged cardiomyocytes and the repair of damaged extracellular matrix (ECM) are highly sought-after therapeutic strategies. Cell transplantation in ECM scaffolds has been shown to improve retention, phenotype, and function in vascular and muscle repair. In addition to cellular patches that involve the use of biomaterial scaffolds in combination with cells, acellular patches may have a role in intrinsically recruiting cells to damaged areas. This review focuses on the clinically relevant ECM scaffolds, their interactions with cells to stimulate functions such as adhesion, migration, proliferation, and differentiation, and their intrinsic role in ECM remodeling leading to vascular and possibly myocardial repair.

Engineered tissue constructs are inherently limited by their lack of microvascularization. Evidence suggests that combining a scaffold material with cells and their cell-secreted signals instigates tubule formation, and various strategies can be employed to tailor the vascular response. This review focuses on rationally designed materials capable of supporting functional neovessel formation and stabilization. Biomaterial scaffolds and their use as growth factor delivery systems are discussed, as well as other functional enhancement strategies to direct cellular responses for effective formation of a mature vascular network.

Myocardial repair remains a major challenge for both cellular and tissue engineering approaches. Several studies have been conducted looking at utilizing extracellular matrix-based therapies to promote repair after a myocardial infarction. In this review, strategies for treating myocardial infarctions using extracellular matrix-derived peptides are discussed. Using an ischemia/reperfusion myocardial infarction rodent model, we showed that extracellular-matrix-derived peptides were able to induce angiogenesis and alter the negative remodeling seen after a myocardial infarction. This therapy opens up a potentially new non-invasive strategy for repairing damaged cardiac tissue.

Cardiovascular disease (CVD) is a leading cause of death and hospitalization worldwide. The need for small caliber vessels (<6mm) to treat CVD patients has grown; however the availability of autologous vessels in cardiac and peripheral bypass candidates is limited. The search for an alternative vessel source is widespread with both natural and synthetic tissue engineered materials being investigated as scaffolds. Despite decades of exhaustive studies with decellularized extracellular matrices (ECM) and synthetic graft materials, the field remains in search of a commercially viable biomaterial construct substitute. While the previous materials have been assessed by evaluating their compatibility with fibroblasts, smooth muscle cells and endothelial cells, current materials are being conceived based on their interactions with stem cells, progenitor cells and monocytes, as the latter may hold the key to repair and regeneration. The graft's ability to recruit and maintain these cells has become a major research focus. The successful tissue engineering of a small caliber vessel graft requires the use of optimal material chemistry and biological function to promote cell recruitment into the graft while maintaining each functional phenotype during vessel tissue maturation. The discussion of these significant research challenges constitutes the focus of this review.

Arteriosclerotic cardiovascular diseases are among the leading causes of morbidity and mortality worldwide. Therapeutic angiogenesis aims to treat ischemic myocardial and peripheral tissues by delivery of recombinant proteins, genes, or cells to promote neoangiogenesis. Concerns regarding the safety, side effects, and efficacy of protein and gene transfer studies have led to the development of cell-based therapies as alternative approaches to induce vascular regeneration and to improve function of damaged tissue. Cell-based therapies may be improved by the application of imaging technologies that allow investigators to track the location, engraftment, and survival of the administered cell population. The past decade of investigations has produced promising clinical data regarding cell therapy, but design of trials and evaluation of treatments stand to be improved by emerging insight from imaging studies. Here, we provide an overview of pre-clinical and clinical experience using cell-based therapies to promote vascular regeneration in the treatment of peripheral arterial disease. We also review four major imaging modalities and underscore the importance of in vivo analysis of cell fate for a full understanding of functional outcomes.

Current evidence suggests that chronic kidney disease (CKD) is associated with an excess risk for cardiovascular disease (CVD) events. In patients with stage 3 CKD (estimated glomerular filtration rate-eGFR 30-59 ml/min/1.73m2) lifestyle measures and appropriate drugs may reduce CVD risk and stabilize (or even reverse) renal function deterioration. Furthermore, CKD is included in recent international guidelines as a population at high CVD risk. The aim should be to effectively reduce CVD risk as well as progression of CKD.

This review provides a systematic overview of the influence of the third generation beta-adrenoceptor antagonists on vascular and/or endothelial function at a cellular level as well as of the advantages of their application in hypertension, heart failure and coronary artery disease. Drugs antagonizing the beta-adrenoceptors have been in use for the treatment of hypertension for decades. In systolic heart failure and post-myocardial infarction, beta-adrenoceptor antagonists were proven to be effective in decreasing the number of deaths and improving morbidity. However, betaadrenoceptor antagonists are a heterogeneous drug group, consisting of agents with different selectivity for adrenoceptors and/or additional effects in heart and peripheral circulation. Beta-adrenoceptor antagonists comprise a multitude of different agents, which may have additional properties exceeding the pure receptor blockade. These features may provide additional benefit in the treatment of hypertension. The third generation drug nebivolol exerts a nitric oxide-mediated vasodilating activity which has positive effects on intima and media thickness and arterial rigidity, a major risk factor in cardiovascular disease. Moreover, anti-proliferative, anti-inflammatory, and anti-oxidative properties have been detected for carvedilol and nebivolol, contributing to their additional value in treatment of hypertension and heart failure.