Preface

The endothelium, the inner vascular layer, is far from being solely a mechanical barrier be‐ cause it enables communication between blood and tissues. In many ways, including its metabolic, secretory, permeability, and vascular tone regulatory roles, it has been implicated as a highly active organ, importantly contributing to cardiovascular homeostasis. Because tissues depend on proper vascularization, the endothelium could indeed be considered as one of the main determinants of tissue perfusion. It actually exhibits immense heterogeneity, which could partly expain its many different functions and roles.

An immense expansion of knowledge on endothelial structure and function was achieved by the discovery of electron microscopy combined with various labeling techniques. Never‐ theless, there are many obscurities regarding *in vivo* studies, even more so in humans. Re‐ spectively, it is not always easy to extrapolate the observations obtained in animal or cell culture studies to humans, leaving a number of unanswered questions.

Exposed to instantanously changing environments and influences, the endothelium is sus‐ ceptible to noxious stimuli, which may lead to endothelial dysfunction. The latter is immi‐ nently connected also to normal aging and has nowadays been recognized as the leading cause of atherosclerosis development predisposing to cardiovascular diseases. Therefore, an insight into molecular mechanisms of endothelial activity is crucial from a clinical point of view because early detection of endothelial dysfunction might postpone the development of disease. Currently, clinical evaluation of endothelial dysfunction remains to be accomplish‐ ed, appropriate clinical methods to timely and accurately detect endothelial dysfunction are lacking, and only more or less robust estimations are available. It is therefore essential to pursue investigations into endothelial function and dysfunction. Accordingly, this book presents recent findings on certain aspects of endothelial (dys)function and the mechanisms involved, as well as potential therapeutic targets involving endothelium and surrogate markers for estimation of endothelial (dys)function.

The book consists of 17 chapters written by reputed authors; because it is impossible to cover all aspects of endothelial function, the chapters present only selected topics. It starts with an introduction by the editor briefly presenting basic characteristics of endothelial structure and function relevant for subsequent chapters. The chapter written by Claudio Aguayo and coau‐ thors follows, addressing genetic aspects with a focus on the Hox gene family directing endo‐ thelial differentiation and angiogenesis. The process of endothelial cell senescence as one of the main causes of the development of endothelial dysfunction is presented by Carracedo, while the chapter written by Wang and coauthors extensively exposes the regulation and function of the longevity regulator sirtuin, proposing also its potential role as an antiaging regulator. Subsequent chapters comprehensively present endothelial elements involved in shear stress sensing, such as the endothelial cilium, described by Escudero and coauthors, and the glycocalyx by Ziganshina and coauthors, and some pathologies associated with their mal‐ functioning. The mechanisms of the von Willebrand factor action and its involvement in thrombotic and inflammatory diseases is outlined in the chapter written by Rusu and Min‐ shall. It has long been appreciated that hyperglycemia adversely impacts the endothelium; accordingly, the chapters by Domokos and Alvarez and coauthors extensively describe the hyperglycemia-associated mechanisms that lead to endothelial dysfunction and expose an important role of oxidative stress. Some altered endothelial metabolic pathways in diabetes and their link to atherosclerosis are also covered in the chapter by Sena and coauthors. The chapter by Korybalska deals with the impact of caloric restriction on endothelial dysfunction focusing on angiogenesis in adipose tissue. Peculiarities of pulmonary endothelium and en‐ dothelial dysfunction associated with respiratory diseases are outlined in the chapters by Gonzales and Verin and Nevzorova and coauthors, the latter focusing on their connection to smoking. The chapter by Sousa and Diniz presents important crosstalk between the endothe‐ lium and the sympathetic nervous system. The mechanisms of HIV-1-infected cells in sustain‐ ing an aberrant endothelial cell function are outlined by Caccuri and coauthors followed by the chapter by Aerts and coauthors who extensively describe the impact of ionizing radiation on the endothelium. The last chapter by Drenjančević and coauthors exposes some potential markers for clinical evaluation of endothelial activation and dysfunction.

I would like to express my gratitude to all authors for their excellent and dedicated reviews, which readers will hopefully enjoy as much as I did. Finally, I'd like to thank the publishing process managers, Mrs Renata Sliva and Mrs Lada Božić, for their help and patience, and InTech publishers for inviting me to be the editor of this book.

I hope that the chapters will be useful for anyone interested in recapitulating endothelial (patho)physiology and expanding the knowledge of molecular mechanisms involved in en‐ dothelial function and dysfunction, and will hopefully uncover additional questions for fur‐ ther, potentially more clinically oriented, investigations.

**Helena Lenasi, MD, PhD**

**Chapter 1**

**Provisional chapter**

**Endothelium at a Glance**

**Endothelium at a Glance**

http://dx.doi.org/10.5772/intechopen.81286

**1. Introduction: general concepts**

an area of 300 m2

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

DOI: 10.5772/intechopen.81286

Exposed to the blood milieu and variable hemodynamic forces, endothelial cells of different vessels exhibit significant heterogeneity, directing also the variety of endothelial functions. Endothelial cells are actively involved in many physiological processes, including vascular tone regulation, fluid filtration and reabsorption processes, maintenance of blood fluidity and proper hemostasis, leucocyte trafficking, tissue repair, and angiogenesis; accordingly, healthy endothelium is crucial for vascular homeostasis. On the other hand, many exo- and endogenous harmful factors can cause endothelial dysfunction, associated with inflammation, thrombosis, pathological vascular wall remodeling, and predisposing to the development of cardiovascular and other diseases. In order to design accurate clinical and pharmacological strategies to postpone or ameliorate endothelial dysfunction, endothelial dysfunction should firstly be recognized. Therefore, understanding endothelial physiology is crucial for clinical measures to be timely taken. The review briefly outlines some basic concepts of endothelial structure and function, focusing on endothelial barrier function and endothelium-dependent vasodilation, and addressing some potential therapeutic targets. Additional specific concepts of endothelial (dys)function, with particular emphasis on its involvement in inflammation, hemostasis, and its (mal)adaptation to environmental challenges are extensively described in the following book chapters.

**Keywords:** endothelium, endothelial cells, endothelial dysfunction, vascular tone regulation, nitric oxide, capillary permeability, cardiovascular diseases, oxidative stress

Endothelium, composed of approximately one trillion endothelial cells and extending over

lymphatic vessels, and the heart. Its strategic position, being in a direct contact with the blood on one side and with the underlying tissues on the other, enables its communication with

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

[1, 2], is a monolayer cell lining covering the luminal surface of blood and

Helena Lenasi

Helena Lenasi

**Abstract**

Assistant Professor of Physiology University of Ljubljana Faculty of Medicine Institute of Physiology Ljubljana, Slovenia

#### **Chapter 1 Provisional chapter**

#### **Endothelium at a Glance Endothelium at a Glance**

#### Helena Lenasi Helena Lenasi

shear stress sensing, such as the endothelial cilium, described by Escudero and coauthors, and the glycocalyx by Ziganshina and coauthors, and some pathologies associated with their mal‐ functioning. The mechanisms of the von Willebrand factor action and its involvement in thrombotic and inflammatory diseases is outlined in the chapter written by Rusu and Min‐ shall. It has long been appreciated that hyperglycemia adversely impacts the endothelium; accordingly, the chapters by Domokos and Alvarez and coauthors extensively describe the hyperglycemia-associated mechanisms that lead to endothelial dysfunction and expose an important role of oxidative stress. Some altered endothelial metabolic pathways in diabetes and their link to atherosclerosis are also covered in the chapter by Sena and coauthors. The chapter by Korybalska deals with the impact of caloric restriction on endothelial dysfunction focusing on angiogenesis in adipose tissue. Peculiarities of pulmonary endothelium and en‐ dothelial dysfunction associated with respiratory diseases are outlined in the chapters by Gonzales and Verin and Nevzorova and coauthors, the latter focusing on their connection to smoking. The chapter by Sousa and Diniz presents important crosstalk between the endothe‐ lium and the sympathetic nervous system. The mechanisms of HIV-1-infected cells in sustain‐ ing an aberrant endothelial cell function are outlined by Caccuri and coauthors followed by the chapter by Aerts and coauthors who extensively describe the impact of ionizing radiation on the endothelium. The last chapter by Drenjančević and coauthors exposes some potential

I would like to express my gratitude to all authors for their excellent and dedicated reviews, which readers will hopefully enjoy as much as I did. Finally, I'd like to thank the publishing process managers, Mrs Renata Sliva and Mrs Lada Božić, for their help and patience, and

I hope that the chapters will be useful for anyone interested in recapitulating endothelial (patho)physiology and expanding the knowledge of molecular mechanisms involved in en‐ dothelial function and dysfunction, and will hopefully uncover additional questions for fur‐

**Helena Lenasi, MD, PhD**

University of Ljubljana Faculty of Medicine Institute of Physiology Ljubljana, Slovenia

Assistant Professor of Physiology

markers for clinical evaluation of endothelial activation and dysfunction.

InTech publishers for inviting me to be the editor of this book.

ther, potentially more clinically oriented, investigations.

X Preface

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.81286

#### **Abstract**

Exposed to the blood milieu and variable hemodynamic forces, endothelial cells of different vessels exhibit significant heterogeneity, directing also the variety of endothelial functions. Endothelial cells are actively involved in many physiological processes, including vascular tone regulation, fluid filtration and reabsorption processes, maintenance of blood fluidity and proper hemostasis, leucocyte trafficking, tissue repair, and angiogenesis; accordingly, healthy endothelium is crucial for vascular homeostasis. On the other hand, many exo- and endogenous harmful factors can cause endothelial dysfunction, associated with inflammation, thrombosis, pathological vascular wall remodeling, and predisposing to the development of cardiovascular and other diseases. In order to design accurate clinical and pharmacological strategies to postpone or ameliorate endothelial dysfunction, endothelial dysfunction should firstly be recognized. Therefore, understanding endothelial physiology is crucial for clinical measures to be timely taken. The review briefly outlines some basic concepts of endothelial structure and function, focusing on endothelial barrier function and endothelium-dependent vasodilation, and addressing some potential therapeutic targets. Additional specific concepts of endothelial (dys)function, with particular emphasis on its involvement in inflammation, hemostasis, and its (mal)adaptation to environmental challenges are extensively described in the following book chapters.

DOI: 10.5772/intechopen.81286

**Keywords:** endothelium, endothelial cells, endothelial dysfunction, vascular tone regulation, nitric oxide, capillary permeability, cardiovascular diseases, oxidative stress

#### **1. Introduction: general concepts**

Endothelium, composed of approximately one trillion endothelial cells and extending over an area of 300 m2 [1, 2], is a monolayer cell lining covering the luminal surface of blood and lymphatic vessels, and the heart. Its strategic position, being in a direct contact with the blood on one side and with the underlying tissues on the other, enables its communication with

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

blood elements and the adjacent cells. Developmentally, it arises from mesoderm via the differentiation of hemangioblasts and angioblasts [3]. However, other cell lineages, such as adipose lineage and mesenchymal cells, can transdifferentiate into endothelial cells even in adulthood [4, 5].

The vast heterogeneity of the endothelium of arteries and veins could additionally be explained by significantly different physiological and physical conditions to which endothelial cells of various vascular beds are exposed, such as blood pressure, shear stress, and pulsatility. Hemodynamic forces significantly impact endothelial structure and function: compared to ellipsoid morphology and coaxial alignment under the conditions of laminar flow, cell morphology and alignment change drastically in the settings of turbulent flow and at vessel

Endothelium at a Glance

3

http://dx.doi.org/10.5772/intechopen.81286

Endothelial cells therefore exhibit a wide range of plasticity, from alterations in the expression of various membrane receptors and adhesion molecules, changes in their morphology and shape, their mitogenic potential and even their potential to migrate or transit into different

Being directly exposed to intravascular milieu, it is obvious that the composition of blood and the (patho)physiological conditions strongly affect endothelial cells, in terms of mediating signals which directly target their surface and activate numerous intracellular signaling pathways. During our life span, we are exposed to a variety of risk factors and toxic and noxious stimuli from the external environment (including air pollutants, tobacco smoke, chemicals from food, radiation, different eating habits in terms of high salt, sugar or saturated fatty acids intake, etc.) which strongly impact endothelial cells and their functions. As such, endothelial cells are constantly being challenged by changing internal environment to which they adapt more or less successfully. As long as their adaptive capacity in terms of maintaining homeostasis between vasoconstrictors and vasodilators reflecting vascular tone regulation; anti- and procoagulant activity reflecting hemostatic processes; anti- and pro-inflammatory mediators affecting the inflammatory response, and pro- and antiangiogenic factors affecting new vessel formation, remains in physiological limits, one might consider the endothelium to be healthy. However, the delineation between health and disease is not easy to define. When the maladaptive patterns overweigh, endothelial dysfunction issues what leads to disease [12].

Although the mostly exposed clinical sign of endothelial dysfunction is impaired endothelium-dependent vasodilation, endothelial dysfunction on a broader scale encompasses a pro-inflammatory, proadhesive, procoagulant, and proliferative state predisposing to atherosclerosis [13]. Multiple mechanisms have been involved in the development of endothelial dysfunction, connected to alterations in glucose and lipid metabolism, insulin resistance, obesity, dyslipidemia, hyperhomocysteinemia, altered hormone and cytokine secretion, imbalance in the autonomic nervous system activity, arterial hypertension, etc. Oxidative stress is acknowledged to play a central role in the development of endothelial dysfunction; moreover, oxidative stress has been appreciated as one of the main factors involved in normal aging, which imminently is also associated with endothelial dysfunction [14]. Although the severity of endothelial dysfunction might differ between vascular beds, independent studies have shown correlations between endothelial dysfunction in different vascular beds [13, 15]. Therefore, endothelial dysfunction can be regarded as a systemic disorder: as tissues and organs depend on proper vascularization and an adequate supply of nutrients and removal of waste products, the dysfunctional endothelium not only predisposes to the development of cardiovascular diseases (atherosclerosis, hypertension, peripheral arterial disease, stroke,

bifurcations, all predisposing to atherogenicity [9, 10].

cell types (endothelial-to-mesenchymal transition) [3, 11].

**1.2. Endothelial dysfunction**

Besides presenting a mechanical barrier between the blood and the tissues, the endothelium is actively involved in various processes, including the regulation of vascular tone, maintaining blood fluidity, and enabling proper hemostasis when needed, in leucocyte trafficking, inflammation, wound repair, and angiogenesis, and, therefore, is of crucial importance for vascular homeostasis. As it metabolizes and releases many physiologically active substances that by acting in auto-, para-, and endocrine manner, govern the above physiological processes, it might justified be called an endocrine organ.
