Current Angiogenesis (Discontinued) - Volume 1, Issue 3, 2012

Radiation therapy or the combination of radiation and chemotherapy is an important component in the local control of many tumor types including glioblastoma, rectal cancer, and pancreatic cancer. The addition of anti-angiogenic agents to chemotherapy is now standard treatment for a variety of metastatic cancers including colorectal cancer and nonsquamous cell lung cancer. Anti-angiogenic agents can increase the efficacy of radiation or chemoradiation for primary tumors through mechanisms such as vascular normalization and augmentation of endothelial cell injury. The most commonly used anti-angiogenic drug, bevacizumab, is a humanized monoclonal antibody that binds and neutralizes vascular endothelial growth factor A (VEGF-A). Dozens of preclinical studies nearly uniformly demonstrate that inhibition of VEGF-A or its receptors potentiates the effects of radiation therapy against solid tumors, and this potentiation is generally independent of the type or schedule of radiation and timing of VEGF-A inhibitor delivery. There are now several clinical trials combining bevacizumab with radiation or chemoradiation for the local control of various primary, recurrent, and metastatic tumors, and many of these early trials show encouraging results. Some added toxicities occur with the delivery of bevacizumab but common toxicities such as hypertension and proteinuria are generally easily managed while severe toxicities are rare. In the future, bevacizumab and other anti-angiogenic agents may become common additions to radiation and chemoradiation regimens for tumors that are difficult to locally control.

Tissue engineering uses various approaches to restore bone loss and heal critical-size defects resulting from trauma, infection, tumor resection or other musculoskeletal diseases. The success of bone tissue engineering strategies critically depends on the extent of blood vessel infiltration into the scaffolds. It has been demonstrated that blood vessel invasion from the host tissue into scaffolds is limited to a depth of several hundred micrometers. Limited vessel perfusion restricts the formation of bone in central regions of the scaffold, leads to loss of cell viability in this region and ultimately does not support healing of the defect. This review addresses the importance of vascularization in bone tissue engineering, discusses the key factors regulating the process of angiogenesis, and provides an overview of current approaches to direct blood vessel formation in biomaterials.

In recent years several molecular and cellular mechanisms have been elucidated that regulate angiogenesis and vascular development. As a result some therapeutic interventions are now available with the potential to enhance normal vascular development and/or to modulate vascular-based disease. The nuclear hormone receptor PPARγ and its clinically useful pharmacologic ligands also modulate angiogenesis and vascular development by actions on both endothelial cells and other cell types. This involves specific effects on the molecular interaction partners and target genes of PPARγ, compensatory changes in processes primarily regulated by other proteins including other PPAR family members, coactivators and corepressors, and “off target” effects involving other signaling pathways. Despite this progress, several factors interfere with determining the specific functions of PPARγ in blood vessel formation and thus with developing PPARγ-based strategies to modulate angiogenesis and vascular development for therapeutic benefit. This review summarizes current proposals for PPARγ functions in angiogenesis and vascular development and emphasizes the complexity of PPARγ gene expression, molecular isoforms with unique functions and unknown expression patterns, the paucity of physiologically relevant endogenous ligands, uncertainties about the specificity of exogenous ligands, and the complex molecular interactions of PPARγ with coregulators and other modifiers. These features are likely responsible for many of the conflicting results obtained in studies of PPARγ in blood vessels and other tissues. Considering these challenges suggests new experimental approaches and future scientific directions that should support significant benefits in a variety of clinical settings involving angiogenesis and vascular development.

It is now widely accepted that tumors are a complex tissue composed, in addition to the cancer cells, by endothelial cells and their precursors, stromal cells, pericytes, smooth muscle cells, fibroblasts, myofibroblasts. Inflammatory and immune cells such as macrophages, neutrophils, granulocytes, mast cells, B and T cells, natural killer (NK) and dendritic cells also infiltrate the tumor to constitute the microenvironment. All these players interact with each other and with tumor cells through specific molecular pathways resulting in the production of an intricate network of molecular mediators, cytokines and growth factors providing the proper conditions for tumor maintenance, growth and propagation. Several pathways of cell-cell interactions within the microenvironment have been previously investigated and extensively studied in physiological and pathological scenarios. Some of these pathways can be targeted with therapeutic drugs during tumor progression. However, a more efficacious approach would be to halt tumor-host interactions before a cancer develops or metastasizes. Many phytochemicals and diet derivatives are able to act as chemopreventive agents, targeting the tumor microenvironment and in particular inflammatory angiogenesis, in a new discipline that we named “angioprevention”. In this review we analyze some of the potential phytochemical drugs, natural or synthetic, that seem to owe part of their chemopreventive potential to their action on the tumor microenvironment. In particular, we provide an overview of the pathways regulated by chemopreventive microenvironment-active substances: oleanic acid triterpenoids (CDDOs), resveratrol, epigallocathechin gallate (EGCG), xanthohumol and curcumin.

Vasculogenesis is characterized by the emergence of angioblasts within the mesoderm and their coalescence into primitive blood vessels, at or near the sites where they originate [1]. Although seemingly simple by definition, studies throughout the years have revealed vasculogenesis to be a complex, multistep process, which is only beginning to be understood at the molecular and cellular level. From specification, to migration, patterning, adhesion and tubulogenesis, myriad signaling pathways and cellular responses must be coordinated to construct a cohesive, contiguous and functional network of tubes to carry blood. Vasculogenesis is not only essential to embryonic blood vessel development, but it is also plays a number of roles in adult pathologies. This review will discuss key steps during vasculogenesis and assess areas of future research interest within the greater clinical context.

Bone morphogenetic proteins (BMPs), members of the transforming growth factor β (TGF-β) superfamily, are multifunctional secreted growth factors that are essential for coordinating complex developmental processes. Recent advances using genetic and molecular approaches have recognized a previously underappreciated angiogenic role for BMP signaling during vascular development and vascular disease. Compelling evidence includes the discovery of mutations in BMP signaling components that have been found in patients with human hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH). A comprehensive review of in vivo and in vitro studies has revealed that the angiogenic response to BMP signaling is context and ligand dependent. This review provides details on these studies as the field moves towards BMP-mediated therapeutic intervention of human vascular diseases.

Angiogenesis is the growth and proliferation of blood vessels from existing vascular structures deputed to repair injured endothelium. Both unselected bone marrow-derived mononuclear cells, which include stem/progenitor cells and several other cell types, and endothelial progenitor cells (EPCs), a subpopulation, show regenerative potential in ischemic injured tissue. In addition, evidence supports both the involvement of EPCs in capillary growth and EPCs participation in the formation of collateral vessels. Accumulating evidence indicates specifically that EPCs derived from bone marrow contribute to reendothelialization of injured vessels as well as neo-vascularization of ischemic lesions. Moreover, the number and/or the functional activity of EPCs inversely correlate with risk factors of cardiovascular disease. Among the different risk factors, cigarette smoking is a major cause of reducing the numbers and function of circulating EPCs as several reports seem to demonstrate. Nicotine plays a strong role in damaging EPCs preparing the following action of carbon monoxide on altered endothelial cells not protected by EPC activity.

Optical imaging has emerged as a method of choice for a number of anatomical and physiological studies, especially in animal models. Optical methods offer distinct advantages such as high spatio-temporal resolution, wide array of available contrast moieties (such as fluorescent dyes, microspheres etc.) and the capability of quantitative “functional imaging”. In this review, we focus on techniques that are adept for imaging microvascular morphology and perfusion. Measures of the microvascular architecture include the number, spacing, density and radii of blood vessels. Perfusion indices include the relative and absolute microvascular blood flow and metrics derived from tracer kinetic theory, such as the mean transit time. Following detailed descriptions of the biophysics of different optical imaging approaches, we conclude with a systematic comparison of the strengths and weakness of each depending on the intended application. We believe this review will serve as a useful starting point for anyone interested in the pre-clinical characterization of microvascular morphology and perfusion in health and disease.