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This volume describes and discusses recent advances in angiogenesis research. The chapters are organized to address all biological length scales of angiogenesis: molecular, cellular and tissue in both in vivo and in vitro settings. Specific emphasis is given to novel methodologies and biomaterials that have been developed and applied to angiogenesis research. Angiogenesis experts from diverse fields including engineering, cell and developmental biology, chemistry and physics will be invited to contribute chapters which focus on the mechanical and chemical signals which affect and promote angiogenesis.



Mechanical and Chemical Regulation of Arterial and Venous Specification

The fact that blood circulates through vessels was realized by William Harvey in the early seventeenth century. The blood flows away from the heart via arteries delivering oxygen and nutrients to peripheral organs and return to the heart via veins. Until late the 1990s, the distinction between artery and vein was recognized solely based on anatomical and function differences, basis, and it had been believed that arterial and venous specific characteristics are controlled by the respective hemodynamic forces that they are exposed to. However, in the past 15 years or so, it has become clear that they are also distinguished by the molecules that they express. Furthermore, their phenotypes are also regulated by genetic, hence, molecular (chemical), programs. In this chapter, I will summarize historical perspectives of the recognition of arteries and veins, and will review recent advance in our understating of mechanisms underlying arterial and venous specification mediated by mechanical and chemical signals. I conclude this chapter by proposing three models, morphogenetic, habituation, and integrative models, explaining how these two classes of signals become integrated to specify arteries and veins.
Thomas N. Sato

Mechanosensory Pathways in Angiocrine Mediated Tissue Regeneration

Endothelial cells not only form the vascular networks that deliver nutrients and oxygen throughout the body, they also establish instructive niches that stimulate organ regeneration through elaboration of paracrine trophogens. Priming of the vascular niche promotes repair and regeneration of damaged tissues by establishing an inductive vascular network that temporally precedes new tissue formation. This induction of endothelial cells provides a platform for essential instructive cues. Tissue regeneration in certain organs such as the liver, involves cell mitosis and expansion, which is orchestrated by a dynamic interplay between cytokines, growth factors, and metabolic pathways. Although the intrinsic events of cell mitosis have been thoroughly studied, the extrinsic triggers for initiation and termination of liver regeneration, especially the set points rendered by the original liver size, are unknown. Furthermore, the gatekeepers that control organ size remain unidentified. The prevailing dogma states that liver regeneration involves the proliferation of parenchymal hepatocytes and nonparenchymal cells such as biliary epithelial cells. However, recent findings also implicate hepatic sinusoidal endothelial cells (SECs) as drivers of this process. In the classic liver regeneration model, in which 70 % partial hepatectomy induces regeneration, the abrupt increase in blood flow into the sinusoidal vasculature of the liver’s remaining lobes correlates with initiation of the regeneration cascade. As such, the shear stress and mechanical stretch exerted on the endothelial cells may activate mechanosensory mediated molecular programs, and may be involved in the elaboration of endothelial cell-derived angiocrine growth cues that support hepatocyte proliferation. Physiological liver regeneration would therefore depend on the proper inductive and proliferative functioning of liver SECs. Thus, uncovering the cellular mechanisms by which organisms recognize and respond to tissue damage remains an important step towards developing therapeutic strategies to promote organ regeneration. In this chapter, we demonstrate the mechanism by which tissue-specific subsets of endothelial cells promote organ regeneration, and further discuss the roles of physical forces and molecular signals in initiating and terminating angiocrine-mediated tissue regeneration.
Sina Y. Rabbany, Bi-Sen Ding, Clemence Larroche, Shahin Rafii

Microfluidic Devices for Quantifying the Role of Soluble Gradients in Early Angiogenesis

Early angiogenesis, as defined by endothelial polarization and directional sprouting, is regulated by gradients of soluble factors in addition to a multitude of other anisotropic cues including interstitial flow, insoluble gradients, and topography of the extracellular matrix (ECM). Adding to this complexity, other microenvironmental inputs, such as matrix density and rigidity, are known to modulate the extent to which vascular endothelial cells react to these anisotropic cues. Given this complexity, novel platforms are needed to decouple and systematically assess signals regulating early angiogenesis. To this end, we discuss a microfluidic device that achieves stable, matrix-independent soluble gradients via passive diffusion, which shields the culture chamber from shear-induced anisotropy. These devices enable direct time-lapse imaging of single cell and collective cell phenomena within both two-dimensional (2D) and three-dimensional (3D) cultures. These experimental platforms have been used to quantify the growth factor concentration requirements that induce endothelial cell chemotaxis, to identify previously unknown regulators of brain angiogenesis, to screen biomaterials for their angiogenic potential, and to investigate the navigational ability of nascent sprouts.
Patrick Benitez, Sarah Heilshorn

Reactive Oxygen Species in Physiologic and Pathologic Angiogenesis

Reactive oxygen species (ROS), including superoxide and hydrogen peroxide, play a major role in angiogenesis. High ROS doses induce oxidative stress and subsequent cell death in a variety of cardiovascular diseases, including hypertension and atherosclerosis. However, low doses of externally applied ROS directly promote angiogenesis by causing sub-lethal cell membrane damage and subsequent fibroblast growth factor-2 release, by increasing growth factor production, or by enhancing growth factor binding to their receptors. Once angiogenic growth factor signaling is initiated, ROS are produced intracellularly through NAD(P)H oxidases and manganese superoxide dismutase as messengers in downstream growth factor signaling for proliferation, migration, and tube formation. This chapter discusses our current understanding of the vascular ROS balance in both physiologic and pathologic angiogenesis, as well as innovative approaches to applying ROS to induce angiogenesis.
Alisa Morss Clyne

Microfluidic Devices for Angiogenesis

Cell culture has played a central role in developing our understanding of angiogenesis, and a wide variety of culture systems have been adapted for this purpose. Despite the value of this approach, many of the systems employed have suffered from a lack of precise control over culture conditions, an inability to visualize the process of angiogenesis in real time, and limitations in the ability to replicate the in vivo situation in which multiple cell types interact over distances of 100s of microns. With the advent of microfluidics, many of these obstacles can be overcome, and in vitro experiments can be produced with closer relevance to the in vivo situation. In this chapter, we describe the evolution of these microfluidic devices in the context of angiogenesis and describe current capabilities.
Vernella Vickerman, Choong Kim, Roger D. Kamm

Vascular Cell Physiology Under Shear Flow: Role of Cell Mechanics and Mechanotransduction

Whether examined at the micro- or macroscale, biological phenomenona are not exempt from physical laws and principles. The vasculature is frequently utilized as a model system to better understand and analyze the consequences of biophysical forces on biochemical processes and ultimate biological phenotypes. Given the complexities of biological systems, there is an inherent need to focus in order to properly elucidate mechanisms. Mechanotransduction and cell mechanics in various stages of angiogenesis have long been examined at distinct length-scales ranging from subcellular, cellular, multi-cellular, tissue, and beyond. This chapter will highlight research over the past decades that have contributed to revealing the importance and interplay between biophysical forces (compressive and shear flow) and biological behavior (motility, regulation of smooth muscle cells, polarity). Abnormal biophysical forces, such as hypertension, contribute significantly to vascular diseases, including atherosclerosis and aneurysm formation. Understanding the relationship between biophysical forces and biological behavior is required to understand the mechanisms of vascular disease.
Devon Scott, Wei Tan, Jerry S. H. Lee, Owen J. T. McCarty, Monica T. Hinds

Matrix Mechanics and Cell Contractility in Angiogenesis

Angiogenesis is a complex process that relies on the interplay of chemical and mechanical signaling events that ultimately result in the formation of new blood vessels. While much work has uncovered the chemical signaling events that mediate angiogenesis, the role of the mechanical environment is less understood. In this chapter, we will discuss how the mechanical microenvironment regulates angiogenesis by examining how matrix stiffness and cellular contractility mediate endothelial cell behaviors that are necessary for the progression of angiogenesis. Specifically, we will describe the roles of matrix stiffness and cell contractility as regulators of endothelial cell adhesion and shape, migration, growth, cell–cell interactions, and cell–matrix remodeling. Collectively, these findings implicate endogenous cellular forces and matrix stiffness as critical components of the angiogenic microenvironment, and suggest that both are important parameters for tissue engineering applications and a greater understanding of angiogenesis during disease progression.
Joseph P. Califano, Cynthia A. Reinhart-King

Computational Modeling of Angiogenesis: Towards a Multi-Scale Understanding of Cell–Cell and Cell–Matrix Interactions

Combined with in vitro and in vivo experiments, mathematical and computational modeling are key to unraveling how mechanical and chemical signaling by endothelial cells coordinates their organization into capillary-like tubes. While in vitro and in vivo experiments can unveil the effects of, for example, environmental changes or gene knockouts, computational models provide a way to formalize and understand the mechanisms underlying these observations. This chapter reviews recent computational approaches to model angiogenesis, and discusses the insights they provide into the mechanisms of angiogenesis. We introduce a new cell-based computational model of an in vitro assay of angiogenic sprouting from endothelial monolayers in fibrin matrices. Endothelial cells are modeled by the Cellular Potts Model, combined with continuum descriptions to model haptotaxis and proteolysis of the extracellular matrix. The computational model demonstrates how a variety of cellular structural properties and behaviors determine the dynamics of tube formation. We aim to extend this model to a multi-scale model in the sense that cells, extracellular matrix and cell-regulation are described at different levels of detail and feedback on each other. Finally we discuss how computational modeling, combined with in vitro and in vivo modeling steers experiments, and how it generates new experimental hypotheses and insights on the mechanics of angiogenesis.
Sonja E. M. Boas, Margriet M. Palm, Pieter Koolwijk, Roeland M. H. Merks

ECM Remodeling in Angiogenesis

Remodeling of the extracellular matrix (ECM) is an essential component of the complex vascular biology that drives each step within the angiogenic cascade. The process of angiogenesis involves a series of events that depend heavily on proteinases and their ability to remodel the ECM, originating with degradation of the basement membrane to allow for endothelial cell (EC) breakthrough, migration, and proliferation. This is followed by organization into nascent blood vessel sprouts, vessel maturation and stabilization, deposition of basement membrane around the new vessels, and finally pruning or remodeling of the new vasculature for physiological needs. There is evidence that ECs cooperate with supporting stromal cells to orchestrate these remodeling events and ultimately to create pericyte-stabilized functional networks of vessels. During angiogenesis, proteinases not only directly breakdown the ECM to create a physical path for new EC sprouts, they also indirectly expose cryptic sites hidden within the ECM to alter the adhesive microenvironment for pericytes and endothelial cells during sprouting. Physiological control of angiogenesis is achieved in part by the angiogenic switch, in which a balance of pro- and anti-angiogenic factors serves to maintain vessel homeostasis under normal conditions. Proteinases, and certain matrix metalloproteinases (MMPs) in particular, function on both sides of the angiogenic switch. They degrade the basement membrane and nearby ECM surrounding established blood vessels at the onset of angiogenesis, and release pro-angiogenic growth factors that would remain otherwise bound to the ECM. However, they also negatively control angiogenesis, as some proteolytic fragments of the ECM possess anti-angiogenic properties. In addition to the chemical specificity of proteinases, emerging evidence suggests that their ability to proteolytically remodel the ECM during angiogenesis may also depend on the physical properties of the ECM. In this chapter, we will discuss the important factors that govern ECM remodeling during angiogenesis, focusing on the links between proteinases, stromal cells, and matrix physical properties. The impact of these possible links on therapeutic and pathologic angiogenesis will also be discussed.
Stephanie J. Grainger, Andrew J. Putnam

Barrier Maintenance in Neovessels

A hallmark of many pathologies is vascular leak. The extent and severity of vascular leakage is broadly mediated by the integrity of the endothelial cell (EC) monolayer, which is in turn governed by three major interactions: cell–cell and cell-substrate contacts, soluble mediators, and biomechanical forces. Despite its tremendous medical importance, no specific therapies are available directly targeting the endothelium to prevent or reduce vascular permeability. Endothelial cells constantly equilibrate contractile and adhesive forces to maintain vascular barrier integrity. Intracellular signalling, and in particular the involvement of small Rho GTPases in endothelial hyperpermeability responses to many inflammatory stimuli through actin/myosin-mediated cellular contractility, is well-understood. Surprisingly less is known about maintenance of the basal endothelial barrier integrity. Recent live cell imaging studies revealed that highly confluent endothelial monolayers actively maintain barrier integrity by a continuous remodeling of their cell–cell contacts, accompanied by a rapid opening and closure of small inter-endothelial gaps. Moreover, evidence is accumulating that mechanical cues determined by the local microenvironment of ECs are of eminent importance to the integrity of the endothelial monolayer. Here we will review chemical and mechanical signaling involved in maintenance of the integrity of the endothelial barrier.
Geerten P. van Nieuw Amerongen

Computational Models of Vascularization and Therapy in Tumor Growth

Computational and mathematical models are powerful tools to study the complexity in biological systems. The models, when validated with experimental evidence, can then be used to better understand the behavior of a complex system subjected to perturbations. In particular, a computational model can be used to test new hypotheses and, in the case of therapies for instance, to predict and optimize treatment outcomes in patients. Most models in biology rely on the description, using continuous or discrete mathematical tools, of the time-course of one or several biological entities. Its aim is to ‘capture’ the dynamics of a process, which by definition evolve in time. Almost all biological processes are characterized by a particular dynamic. Computational modeling relies on the premise that integrating the dynamics of a process can provide benefits in its understanding compared to a classical static analysis.
Benjamin Ribba, Floriane Lignet, Luigi Preziosi

Biomaterials for Cell-Based Therapeutic Angiogenesis

Stem cells and endothelial progenitor cells are increasingly studied for use in therapeutic angiogenesis to treat ischemic tissues and critical-sized tissue defects because of their potential to sustainably express multiple angiogenic factors and also differentiate to endothelial cells. These cells are often incorporated into a variety of biomaterials which can function as a provisional matrix to localize or deploy cells and also to regulate cellular phenotypic activities at a transplantation site. This chapter will summarize previous and current efforts to design cell-laden biomaterials in order to improve therapeutic efficacy of transplanted cells to stimulate revascularization. Finally, it will discuss future strategies of biomaterial design that can further elevate the quality of the cell-based revascularization therapy.
Max H. Rich, Hyunjoon Kong

Translation of Pro-Angiogenic and Anti-Angiogenic Therapies into Clinical Use

Angiogenesis is a central physiological process that establishes blood supply and oxygen supply to tissues, thereby enabling the growth and maintenance of nascent bodily structures. Angiogenic signals function throughout the lifecycle to ensure perfusion, proliferation, and preservation of cells, tissues, and organs. During embryonic development, angiogenesis is absolutely critical; the generation of blood vessels is crucial to the formation of every organ. In adulthood, angiogenesis is necessary for wound healing, as well as recovery from ischemic insults; in such cases, it is beneficial to promote angiogenesis. However, angiogenesis is undesirable and pathological in the context of cancerous tumors, as well as diabetic retinopathy; in these cases, it is preferable to halt angiogenesis. Thus, pro-angiogenic and anti-angiogenic signals must operate in balance to assure physiological health. This chapter reviews current knowledge regarding biochemical regulators of angiogenesis, and highlights molecular targets of pro-angiogenic and anti-angiogenic therapies. The chapter additionally discusses current progress in translating both pro-angiogenic and anti-angiogenic therapeutics into clinical usage, and identifies potential barriers to the clinical introduction of such therapeutics. Finally, the chapter suggests future basic research and clinical research priorities for tailoring angiogenesis to address patient needs.
Sujata K. Bhatia

Erratum to: Reactive Oxygen Species in Physiologic and Pathologic Angiogenesis

Krishna Arjunan, Alisa Morss Clyne


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