Current Angiogenesis (Discontinued) - Volume 3, Issue 1, 2014

Angiogenesis is becoming an important research topic not only for cancer but also for cardiovascular diseases. In recent years, great strides have been made towards understanding the mechanisms associated with the process of angiogenesis, and towards developing effective tools/approaches of treatment for angiogenesis-related diseases (i.e. cancer, inflammation, and cardiovascular disease). In this special issue of the journal, we are pleased to publish three reviews on “Angiogenesis in the Development of Cardiovascular Disease”, edited by Dr. Pallab (Paul) Ganguly. In the first article, Casieri et al. introduce and discuss the regulation of angiogenic gene expression by different epigenetic modifications. It is suggested that pro-angiogenic epigenetic activators are new factors in the modulation of the angiogenic balance of failing hearts. The article summarizes the epigenetic mechanisms involved in the regulation of function and angiogenic ability of mature endothelial cells residing in the adult myocardium. The second paper by Nader et al. discusses the role of cardiomyocytes and macrophages in myocardial angiogenesis. In fact, both cardiac macrophages and cardiomyocytes have the ability to release angiogenic molecules (VEGF and/or ANGPT) in response to inflammation, ischemia or tissue damage. They also review bench-to-beside translational studies involved in delivery of angiogenic genes, growth factors, or stem cells to patients with coronary artery disease (CAD). However, clinical trials using these approaches have been rather equivocal and underscore the need for further work in this area. The third paper by Dr. Abd-Elfattah in the special edition discusses the relationships between stress, cardiovascular disease and surgeryinduced angiogenesis. According to this review article, it is not wise to promote angiogenesis in cases of coronary artery diseases in cancer patients, and vice versa. Future studies should identify the approaches/targets that selectively suppress tumor angiogenesis without affecting cardiovascular angiogenesis. In addition to this special theme, the subsequent three articles move away from angiogenesis in the field of cardiovascular diseases, and raise concerns for “Targeting angiogenesis in the treatment of multiple myeloma” by Dally N and Eshel E; “Platelets in angiogenesis upon healthy and disease conditions” by Schattner et al.; and methods on angiogenesis quantization by Dr. Kavantzas. Specifically, Dally and Eshel highlight important data regarding angiogenesis in Multiple Myeloma (MM) as well as the drugs currently used to target angiogenesis for its treatment. Schattner et al. presents an integrated summary of the current knowledge on the role of platelets in angiogenesis and its consequences in health and disease. The papers in this special issue represent the most updates on myocardial angiogenesis and other angiogenesis-related research findings. We believe that you will find them informative and helpful in your work. We would like to thank all who kindly contributed their papers for this issue and the guest editor: Dr. Paul Ganguly for collecting and editing these review papers.

The role of angiogenesis in the development of cardiovascular diseases has been a great controversy in the recent past. Studies have implicated coronary angiogenesis in the heart growth whereas inhibition of angiogenesis is believed to impair cardiac growth and accelerate cardiac dysfunction. Thus it is suggested that coordinated tissue growth may be related to angiogenesis in which the heart progresses from normal to adaptive cardiac hypertrophy. This physiologic hypertrophy is possible so long as the angiogenesis process is stimulated. Heart failure ensues when angiogenesis is inhibited resulting in disruption of coordinated tissue growth.

The term "Epigenetics" refers to chromatin-based pathways involved in the regulation of gene expression without altering DNA sequence. Suppression of angiogenesis may be related to cardiac dysfunction following alterations in capillary microvasculature. An understanding of the relationship between angiogenesis and cardiac remodeling remains the major limitation in order to address the weak self-renewal ability of the adult failing heart. In physiological conditions, genes responsible for sustaining the angiogenic ability of the mature endothelial cells can be categorized into pro- and anti-angiogenic genes. The balanced expression of angiogenic genes maintains a state of equilibrium in capillary density of the adult myocardium. In the context of post-ischemic myocardial dysfunction, transcriptional and posttranscriptional modifications of the gene pool are involved in alterations of angiogenic balance in capillary microvasculature, angiogenesis, myocardial perfusion/contractility match and contractile function. The regulation of angiogenic gene expression by different epigenetic modifications may induce the formation of new vessels from coronary mature endothelial cells rather than endothelial progenitor cells. The role of proangiogenic epigenetic activators is emerging as a new actor in the modulation of the angiogenic balance of failing heart. In fact, the development of an ideal method to promote myocardial revascularization, while attenuating cardiac remodeling, is still a challenging issue. The present review will examine emerging studies on the epigenetic mechanisms involved in the regulation of function and angiogenic ability of mature endothelial cells residing in the adult myocardium.

Angiogenesis is a natural process that occurs in under-perfused tissues in response to inflammation or low oxygen supply (activation of HIF). Cardiac angiogenesis remains an ultimate approach to avoid irreparable deterioration of cardiomyocytes. The two master angiogenic factors are the vascular endothelial growth factor (VEGF) and angiopoietin 1 and 2 (ANGPT1 and 2). While both VEGF and ANGPT2 are mainly involved in the initiation of angiogenesis, ANGPT1 is essential for the stabilization of the newly formed vessels. Here we review the available information on the role of macrophages and cardiomyocytes in cardiac angiogenesis. Myocardial ischemia leads to a local sterile inflammation that initiates angiogenesis. Both cardiac macrophages and cardiomyocytes have the ability to release angiogenic molecules (VEGF and/or ANGPT) in response to inflammation, ischemia or tissue damage. Bench-to-beside translation of the information obtained has involved delivery of angiogenic genes, growth factors, or stem cells to patients with coronary artery disease (CAD). Clinical trials using these approaches have been rather equivocal and underscore the need for further work in this area.

Vasculogenesis refers to the de novo formation of vessels during embryogenesis, development and tissue repair. Angiogenesis is a biological process by which arteries and veins are developed from pre-existing vessels first developed by vasculogenesis. Both vasculogenesis and angiogenesis processes are also involved in important biological events such as activation, proliferation, migration, and differentiation of endothelial cells. Angiogenesis is also modulated by the interactions of several angiogenic factors, extracellular matrix and medications. Although stimulation of angiogenesis is a favorable process for patients with coronary artery diseases, uncontrollable stimulation of angiogenesis is detrimental in patients with tumor metastasis and organs’ megaly. Recent advances in cancer and ophthalmologic research provided better understanding of neovascularization in common ischemic syndromes. Sudden or gradual changes (stress) in the body or in the surrounding environment trigger biochemical and molecular responses that enable the body to protect it-self first by reducing metabolic demands and second by attempting to resolve the consequences of imposed stress. The focus of this review is to discuss the relationships between stress, cardiovascular disease and surgery-induced angiogenesis. Therapeutic angiogenesis is beneficial to patients with ischemic heart disease by augmenting myocardial blood perfusion. Congenital anomalies of great vessels, valves, arteriovenous channels and anemia are few of many birth defects that cause chronic cyanosis and oxidative stress. Reduced tissue oxygenation triggers a sympathetic stimulation by abrupt release of neurotransmitters forcing the heart to work harder in order to normalize blood perfusion. Anemia, hypertension, coronary artery diseases and electrophysiologic abnormalities also impose hyperdynamic blood circulation and promote angiogenesis. Antihypertensive drugs tend to attenuate the process of angiogenesis while anti-angiogenic drugs tend to induce hypertension suggesting a causal relationship between hemodynamics and development of angiogenesis. Surgical dissection of cancer tumor stimulates angiogenesis and further tumor growth and expansion. Therefore, it is not wise to promote angiogenesis in cases of coronary artery diseases in cancer patients, and vice versa. Eventually, the time shall come when differential targets will be identified to selectively suppress tumor angiogenesis without affecting cardiovascular angiogenesis.

Multiple Myeloma (MM) remains an incurable disease. Scientific understanding of the biology and influence of the microenvironment in disease progression and outcome has led to treatment improvements by targeting angiogenesis. Reviews of the underlying biology and meta-analyses of the clinical data tend to be mutually exclusive. This minireview highlights important data regarding angiogenesis in MM as well as the drugs currently used to target angiogenesis in its treatment.

Increasing experimental and clinical research suggests a role for platelets in angiogenesis. These cells are major storage and delivery vehicles of a broad array of growth factors, chemokines, cytokines, proteases and cell adhesion molecules, which are secreted upon activation and determine the local angiogenic stimulus. Although platelets contain both, pro- and antiangiogenic molecules, there is a general consensus that platelets promote angiogenesis by stimulating chemotaxis, proliferation, and differentiation of endothelial cells and recruitment of progenitor cells to sites of vascular injury. However, a growing body of evidence indicates that the angiogenic proteome of platelets can be modified under stressful microenvironmental conditions such as cancer. How platelets regulate angiogenesis in different clinical scenarios is not completely understood. The amplification of angiogenesis by platelets plays a positive and beneficial role in several processes, such as pregnancy and tissue healing, where new vessel development is required. However, in clinical conditions associated with abnormal or excessive angiogenesis including cancer, atherosclerosis, and arthritis, platelets might contribute to the detrimental progression of these diseases. This review represents an integrated summary of the current knowledge regarding the role of platelets in angiogenesis and its consequences in health and disease.