The Vascular Endothelium: A Holistic Approach for Oncology

By Domenico Ribatti and Francesco Pezzella

The Vascular Endothelium: A Holistic Approach for Oncology provides novel and integrated knowledge on the endothelial cells as a crucial component involved in the growth of different organs in both physiological and pathological conditions. By covering diverse aspects of anatomy, embryology, molecular biology and pathology, it details the important role of the endothelium for the pathogenesis of cancer and how this knowledge can improve the outcome of cancer research.The content is split in six parts: appearance and evolution of the endothelial cell, which discusses for instance comparative anatomy of the endothelium in relation to the vascular system; endothelial cell in embryology and organogenesis, covering the interaction between endothelial and hematopoietic cells; the lymphatic system, which brings information on lymphatic endothelial cell markers and molecular regulation of lymphangiogenesis; the anatomy of the endothelium in adults, showing the differences in the mature endothelial cells through the body; the physiology of the endothelial cells, with organ specific physiological activity of the endothelium; and the endothelial cells in cancer, discussing the use of endothelium as target for treatment and current therapeutic approaches.This book is a valuable resource for cancer researchers, oncologists and other members of biomedical field who are interested to learn more about the complexity of vascular endothelium and its impact on cancer and other related diseases.

• Provides a holistic approach to the knowledge of endothelial cells in different organs, from early years of development to adulthood
• Discusses relevant aspects of endothelial cells related to the pathogenesis of cancer to be applied to novel therapeutics
• Presents an interdisciplinary view of the vascular endothelium, covering anatomy, embryology, molecular biology, pathology and clinical implications

• Language: English
• Publisher: Academic Press
• Release date: May 29, 2022
• ISBN: 9780128243923

Domenico Ribatti

Domenico Ribatti was awarded his M.D. degree in October 1981, with full marks. In 1983, D.R. joined the Medical School as Assistant at the Institute of Human Anatomy, University of Bari. In 1984, he took the specialization in Allergology. In 1989, he spent one year in Geneva, working at the Department of Morphology (Prof. R. Montesano). In 2008, he received the honoris causa degree in Medicine and Pharmacy form the University of Timisoara (Romania). D.R. is author of 866 publications as reported in PUBmed and contributed to 50 chapters to books. Overall, his papers have been cited 51153 times. He has published many books with both Elsevier and Springe

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1: Appearance and evolution of the endothelial cell

Abstract

Once upon a time there was no circulatory system but the need for it arose with the development of multicellular organisms. In the animal kingdom, the vascular system first appeared around 600 million years ago. The endothelial cells evolved later, between 540–510 million year ago, when Vertebrates, the largest subphylum of the Cordate phylum, is believed to have separated from the other two Cordate subphyla, the Urochordata and Cephalochordata. At the same time of the appearance of the endothelium, endothelial heterogeneity also developed as supported by the fact that in the Hagfish, the oldest living vertebrates, the phenotype of the endothelial cells differs trough the body, from organ to organ. An endothelial cell is designated as one covering the luminal space of the vessels, forming a continuous layer having a basal-luminal polarity and these cells are kept adherent to each other, and to the basal membrane, by specialized junctional complexes.

Keywords

Animal species; Endothelium; Evolution; Vascular system

1.1. Appearance of a circulatory system

Once upon a time there was no circulatory system but the need for it arose with the development of multicellular organisms. Living organisms are divided, according to current Taxonomy, into three groups called Domains: Bacteria, Archea end Eukarya (Woese et al., 1990). The Domain Eukarya is divided into seven Supergroups. The Supergroup Land Plants account for the Kingdom Plants while the supergroup Opisthokonta (meaning with posterium flagellum) contains two other Kingdoms: Fungi and Animalia (Metazoa) (Brooker et al., 2014). The supergroup Opisthokonta is characterized by the fact that, when present in the components of this group, cells with a flagellum are able to use it to propel themselves. While unicellular organisms directly exchange nutrients, metabolite and catabolite with the medium they inhabit, the development of larger and/or thicker than, approximately, 1mm organisms has been conditional to establish an adequate system for distribution and disposal of nutrients plus any other molecules linked to their vital functions (Munoz-Chapuli & Perez-Pomares, 2010). Such systems are found both in the Plant and Animal kingdoms although they present very different characteristics.

In the animal kingdom (Fig. 1.1), the vascular system first appeared around 600 million years ago. While smaller than approximately 1 or 2 millimeters, Metazoan could rely effectively on diffusion, larger multicellular organisms needed cavities inside the organism allowing fluids to circulate and transport molecules across the body according to requirement (Monahan-Earley et al., 2013). The endothelial cells evolved later, between 540 and 510 million year ago, when Vertebrates, the largest subphylum of the Cordate phylum, are believed to have separated from the other two Cordate subphilia, the Urochordata and Cephalochordata (Bikfalvi, 2016). At the same time of the appearance of the endothelium, endothelial heterogeneity also developed (Monahan-Earley et al., 2013) as supported by the fact that in the Hagfish, the oldest living vertebrates, the phenotype of the endothelial cells differs through the body from organ to organ (Cheruvu et al., 2007; Shigei et al., 2001).

Presently, in the literature, an endothelial cell is designated as the one covering the luminal space of the vessels, forming a continuous layer (except in some specialized vessel like liver sinusoids) having a basal/luminal polarity and these cells are kept adherent to each other, and to the basement membrane, by specialized junctional complexes (Munoz-Chapuli et al., 2005). It is a striking fact that, when using this definition of endothelium, all the papers published in literature report, and conclude, that vertebrates have proper endothelial cells while the invertebrates do not. It is therefore the current accepted wisdom that the presence of cells called endothelial, according to the above definition, divides invertebrates from vertebrates (Cheruvu et al., 2007), that is, the endothelium and the backbone appear to have evolved together.

Figure 1.1  All the diploblasts and the simpler triploblasts do not have coeloma which appears in large invertebrates (e.g., the Earthworms). The more complex invertebrates evolved, thanks to the development of the Hemel, a proper vascular system with heart/herat like structures. The endothelium is instead a characteristic of the vertebrates: only them, and all of the, have endothelial cells.

In the simplest organisms like the Dipoblasts (Metazoa those embryos have only two layers, the ectoderm and the endoderm), no coelomic cavity or other circulatory structures are seen. Some of the smallest Triploblasts (animals with three embryonal layers: ectoderm, mesoderm and endoderm) also do not have coelomatic cavity. This chamber, the simplest cavitated system to circulate fluids inside a body, starts to appear as the Triploblasts increased in size (Hartenstein & Mandal, 2006). The earliest vessels developed around the gut to collect and transport nutrients, rather than oxygen, with the gases exchange happening through the skin. Later on during evolution, vessels also started to transport and exchange gases. Evolution of the all cardiovascular apparatus is a vast topic (Burggren & Reiber, 2007); therefore, in this chapter, we will focus on the evolutionary development of the endothelial cell. As there are no fossils remains of endothelium, its evolutionary history rely mostly on molecular phylogeny, that is, the comparison of genetic material between species to understand their evolutionary relationship, and on ontogenesis, the study of the development of existing organisms (Aird & Laubichler, 2007; McVey, 2007).

1.2. Coeloma, the basic circulatory system

As mentioned above, early multicellular organisms like flat worms still rely on diffusion. As they do not have even a coelomatic cavity, they are also classified as Acoelomates: all the organs are embedded inside a mesenchymal tissue and liquid-filled, of any type, are absent (Conn, 1993) although some occasional small poorly defined liquid filled spaces can be recognized (Pseudocoelomate) (Monahan-Earley et al., 2013) (Figs. 1.2 and 1.3).

To grow bigger than an Acoelomate, multicellular organisms had to develop a circulatory system, as simple diffusion would not suffice. This happened sometime before 600 million of years ago (Bikfalvi, 2016). Around this time, larger organisms with a fluid-filled body cavity, the coelom, evolved, for example, the earth worms. The walls of this space are formed by tissue from the mesoderm and are lined up with cells which prevent the leaking of the fluid from the cavity into the surrounding mesenchyma. These cells are known as mesothelial, that is, epithelial cells of mesodermal origin, to distinguish them from epithelial cells of either ectodermal or endodermal origin (Bikfalvi, 2016; Holland, 2011). Many of these cells have cilia those movements contribute to the circulation of the fluid. In some metazoan, these coelom-lining cells can have myo-epithelial features, that is, they can also contract increasing the movement of the fluid. In other organisms instead, there are proper muscle cells surrounding the coelom and sustaining the fluid recirculation, with their contractions (Munoz-Chapuli & Perez-Pomares, 2010). Cavity lined by either mesoderm, in some areas, or endoderm, in other locations, are called pseudocoelom (Brooker et al., 2014), not to be confused with the Pseudocoelomate spaces described in the Acoelomate as described above.

Figure 1.2  Basic anatomy of the circulatory systems. (A) Acoelomata diploblasts metazoan has only two embryonal layers: ectoderm and endoderm. The two epithelial layers form a digestive tube and the external epithelium. There is no mesenchyma and no coelomatic cavity. (B) Acoelomata triploblasts have three embryonal layers, ectoderm, endoderm, and mesoderm. (C) Pseudocoelomata with some spaces filled with fluid but no mesothelial lining.

Figure 1.3  Basic anatomy of the circulatory systems. (A) Coelomates are metazoan with a colema: a space lined up by mestothelium filled up by fluid usually containing some hematic cells. The mesothelium can have myoepithelial features or muscle like cells, which are present in the nearby mesenchyma providing contractor movements. (B) In large invertebrates, the Hemel circulatory system develops. These channels are lined by mesodermal extracellular matrix. Some invertebrates can have some cells a lining tracts of vessels but these are Amoebocytes and do not have all the characteristics of the endothelial cells. (C) Vertebrates. The circulatory systems of all vertebrates are instead lined up by a continuous layer of endothelial cells. Coelomatic cavities are still present but do not have any role in circulation.

The coelom has several functions, alongside acting as a primordial circulatory system, including physical protection of internal organs and offering a space for these organs to grow and move in. Nutrients and gasses diffuse from the skin to the fluid inside the cavity, and the fluid is then kept in motion spreading equally the solutes through the body. At the same time, any substance to be excreted is released inside the fluid and subsequently expelled, by diffusion, through the skin. The Coelom is still persistent in larger animals and, in mammals, has developed into the peritoneal, pleural, and pericardiac cavities. These spaces have a fundamental role in allowing organs like the heart or the intestine to move freely while performing their functions.

1.3. The hemel, vascular channel without endothelium

Alongside the Coelom, a channel-based circulatory system started also to evolve, the so-called Hemal System: this is defined by three components: a system of vessels, that is, hollow tubes, a special fluid filling it (blood, hemo-lymph, or lymph) and, finally, the presence of one or more of a modified vascular segment, rich in muscle cells, able to pump the fluid: the heart and its precursors (Brooker et al., 2014) (Figs. 1.2 and 1.3). The cellular component of the Hemel system, mainly the myoepithelial and the circulating cells, is regarded as originating from the coelom epithelium, both in phylogenesis and ontogenesis (Munoz-Chapuli & Perez-Pomares, 2010).

Why was the coelom not enough and, therefore, why did the hemel evolved? One hypothesis is that, when segmented animals started to appear, the formation of vessels was necessary to allow the transport of fluid from the coelom of one segment to that of another one (Monahan-Earley et al., 2013). The presence of an early vascular system does not rule out completely diffusion or the presence of a working coelom (Ruppert & Carle, 1983): for example, the hemel system in insects does not delivery oxygen, and this is done by the tracheal system. The combined hemel-coelom system is found in some invertebrate: in these animals there are heart structures, from which vessels originate, these vessels conduct the fluid to an open cavity, the hemocoel. Here, the fluid, called hemolympha, is subject to exchange of nutrients, catabolites and gas than the fluid return to the heart. Two are the anatomical structures delivering the hemolympha from hemocoel to the heart that can be found. In some organisms, the hemocel is connected to the heart by some downstream channels while in others the hemocel opens directly inside the heart. In more complex animals instead, the vessels and the coelom cavities are separated and an anatomical communication between the two is no longer present (Brooker et al.,