Genesis, Pathophysiology and Management of Venous and Lymphatic Disorders

By N. Radhakrishnan

Genesis, Pathophysiology Management of Venous Diseases is the must-have resource on venous disease. The book bridges the gap between basic science and clinical medicine, covering the history of venous surgery, the lymphatic system and anatomy, pathophysiology of various venous disease, etiology, clinical manifestations and diagnosis, management, and medical and surgical treatment options. It also places attention on genetic studies and pharmacological analysis of various anticoagulants which are widely used in treating venous diseases and deep vein thrombosis and highlights the importance of microscopic venous valves and their pathology in both normal and disease condition.

The breadth of topics covered makes this reference suitable for a range of professionals in phlebolymphology and cardiology, including medical students, practicing clinicians, surgeons, researchers, radiologists, bioengineers, and more.

• Provides complete, up-to-date developments in the field of phlebolymphology, including the history of venous surgery, lymphatic system and anatomy, pathophysiology of various venous disease, and more
• Includes new etiological and pathophysiological concepts and the latest outlooks and trends in the management of CVD
• Written in an easy-to-read manner, the book includes tables, figures, clinical photographs and medical illustrations to aid understanding

• Language: English
• Publisher: Academic Press
• Release date: Jan 4, 2022
• ISBN: 9780323884341

N. Radhakrishnan

N. Radhakrishnan is currently the Medical Director of St. Thomas Institute of Research on Venous Disease, India. Graduated from Trivandrum Medical College, he completed his postgraduate studies in general surgery at the same college, and was a practicing surgeon for 46 years and 52 years as a medical practitioner. With his wealth of experience from being a practicing surgeon, he entered the field of Phlebolymphology and has been Senior Consultant Vascular Surgeon in St. Thomas Hospital, Chethipuzha, Changanassery, Kerala, India since 1980, and was promoted to his current role in 2009. He is a Fellow of Royal College of Surgeons of England, Fellow of Royal Society of Medicine (FRSM-London), Fellow of Royal College of Physicians & Surgeons of Glasgow, Fellow of American College of Surgeons, and Fellow of the IMA Academy of Medical Specialties. He is one of the first Fellow of the International College of Surgeons (Phlebolymphology), and is a founder Fellow of Association of Surgeons of India. He has over 9 peer reviewed publications, and has presented his research findings internationally. He has been presented the Lifetime Achievement Award in 2014 by the President of India for his contributions towards the field, and has won the “Best Doctor Award” in India in 2017. Working with the Rajiv Gandhi Centre for Biotechnology (an autonomous Institute of the Department of Biotechnology, Government of India), his research interests include the genetic factors in venous disease, and developing new medical and surgical technologies in treating venous diseases. In addition, presently doing research project on Bio-Nano Technology for healing of Chronic nonhealing Ulcers in collaboration with Mahatma Gandhi University, Kerala, India.

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Chapter 1

The lymphovenous system

Abstract

In order to understand a disease process in the human body, understanding of basic science plays a significant role. The lymphovenous system is a very complex part of the cardiovascular system. However, it has remained relatively unexplored for centuries. Compared to the venous system, knowledge of the lymphatic system was so primitive that the management of related diseases was hindered. The cardiovascular system is the initial functional organ system formed in mammalian embryos. During development, early structuring of the cardiovascular system network is a complex morphogenetic process which demands the regulation of multiple cell types and the activation of several signal transduction pathways. If this network is not established properly, organ development and embryo viability are affected. Furthermore, maintenance and stabilization of this complex cardiovascular network must occur throughout adulthood, as impairments in vessel integrity and hemodynamic functions can result in poor health and early death. The vascular system forms as a branching network of endothelial cells that inherit their identity as arterial, venous, hemogenic, or lymphatic vessels.

Keywords

Lymphovenous system; signal transduction pathways; vessel integrity; hemodynamic function; endothelial cells; transcriptional control of endothelial differentiation; signal in pathways; intussusceptive angiogenesis; sprouting angiogenesis; vascular endothelial growth factor; network formation; remodeling; pruning; maturation; stabilization

1.1 Embryological considerations

1.1.1 Early embryonic development

The cardiovascular system is the initial functional organ system formed in mammalian embryos. Furthermore, maintenance and stabilization of this complex cardiovascular network must occur throughout adulthood, as impairments in vessel integrity and hemodynamic function can result in poor health or early death [1]. The vascular system forms as a branching network of endothelial cells that inherit their identity as arterial, venous, hemogenic, or lymphatic vessels.

The vascular system initially erupts in the embryo as a highly branched network of structurally primitive vessels composed of endothelial cells and their basement membranes. Embryonic endothelial cells (EEC) express their identity as arterial, venous, lymphatic, or hemogenic components, and then further specialize in an organotypic manner [2] (Fig. 1.1).

Figure 1.1 Transformation of epiblast from mesoderm to mature endothelila cells.

In addition to EEC, erythromyeloid progenitors in the yolk sac give rise to tissue-resident fetal macrophages that play a vital role in the morphogenesis and function of developing angiogenic blood vessels [1].

The primitive erythroid cells circulate within the embryonic vascular network and arise from hemogenic endothelial cells in the yolk sac blood islands around E7.5 [3]. Gradually, these primitive erythroid cells are replaced by definitive erythroid cells. The morphogenesis of the embryonic vascularate commences with the accumulation of presumptive endothelial cells (PECs) into loosely associated cords following their segregation from the mesoderm [4]. In 1915, Raegen showed that blood vessels of the embryo originate within the body proper, not by invasion from the highly vascular extraembryonic yolk sac.

The dorsal aortae and posterior cardinal veins are the first major blood vessels that form in situ by segregation of mesenchymal cells from the mesoderm. The dorsal aortae soon form a continuous cord at the ventrolateral edge of the somites and are continuous into the head to fuse with the ventral aortae forming the first aortic arch by the six-somite stage. The primitive endocardium fuses at the midline above the anterior intestinal portal by the three-somite stage and the ventral aorta extends craniad. Intersomitic arteries begin to sprout from the dorsal aorta at the seven-somite stage. The posterior cardinal veins form from single cells which segregate from the somatic mesoderm at the seven-somite stage to form a loose plexus which moves mediad and wraps around the developing Wolffian duct in later stages [5].

These studies suggest two models of origin of embryonic blood vessels. The dorsal aortae and cardinal veins evidently arise in situ by the local segregation of PECs from the mesoderm. The early vessel rudiments lead to the formation of intersomitic arteries, vertebral arteries, and cephalic vascularate by the process of sprouting. The importance of cell migration in the morphogenesis of endocardium, ventral aorta, and aortic arches is also essential in the development of the vascular network. Highlighting the physical and molecular cues requisite to activate the morphogenetic events that anticipate during vascular development has been a remarkable challenge to cancer biologists, physiologists, scientists, and developmental biologists of many other disciplines for centuries. Elucidating these mechanisms is indispensable for determining how a normal vascular network develops and how aberrant vascular development can contribute to disease conditions [6].

The sprouting form of angiogenesis has been much more comprehensively studied recently as it is the mechanism by which cancer cells recruit a new vascular supply [7]. The angiogenic factors have also been discovered in developing systems. The kidneys and brain produce angiogenic factors which resemble tumor angiogenic factors [8].

1.1.2 Transcriptional control of endothelial differentiation

Two well-defined mechanisms of blood vessel formation in the early embryo have been described. The de novo formation of endothelial cells by differentiation from angioblasts followed by their self-assembly into vascular structures is called vasculogenesis. The process of vasculogenesis is highly dependent on specification of endothelial cell fate from progenitors in the mesoderm via activity of the E26 transformation-specific domain transcription factor (Etv2—also called Ets variant gene 2 or ETSRP71) [2]. The requirement of Etv2 in embryonic angiogenesis, either alone or in combination with other endothelial transcription factors, was addressed by Craig et al. [9] using a zebrafish model of vascular development. The above-mentioned study examined functional interactions between Etv2 and the Ets domain-containing transcription factors Fli 1a and Fli 1b in early vascular development. Embryos double-deficient for Etv2 and Fli 1b failed to form angiogenic sprouts and exhibited greatly increased endothelial apoptosis throughout the developing vasculature. Endothelial specification depends on gene targets transcribed by Ets domain-containing factors, including Etv2, together with the activity of chromatin-remodeling complexes containing Brahma related gene-1 (BRG1) [10].

Once nominative and structured into vessels, mechanisms restricting lumen diameter and axial growth ensure that the structure of the branching vascular network matches the need for perfusion of target tissues. In addition to this mechanism, the important morphogenic cues provided by the blood vessels will guide or alter the development of organs forming around them. Eventually, as the embryo grows and the diameter of the lumen increases, the smooth muscle cells (SMCs) wrap around the nascent vessel walls to provide mechanical strength and vasomotor control of the circulation [11]. Finally, the SMC differentiation via coupling of actin cytoskeleton remodeling to myocardin and serum response factor-dependent transcription is promoted by increased mechanical strength and wall strain.

One essential target for Etv2 in endothelial cells is an Ets factor-binding intronic enhancer element in the gene encoding vascular endothelial growth factor receptor (Flk1/VEGFR2) [2]. This enhancer sequence also contains an essential Gata factor-binding motif that likely interacts with Gata2 in endothelial cells. Etv2 is highly requisite for angiogenesis in adult tissues. Overexpression of Etv2 has been used to direct vascular progenitor cells in the postnatal arterial adventitia toward an endothelial cell fate. The chromatin-remodeling enzyme BRG1 is vital for early vascular development and primitive hematopoiesis [10].

1.1.3 Vascular lumen diameter controlled by endothelial cells

In small arteries and arterioles, the lumen diameter is restricted mainly by myogenic and neurogenic control of vasomotor activity in circumferentially arranged vascular SMCs [12]. In larger conduit arteries, the lumen diameter is primarily restricted by wall remodeling and is blood flow responsive and endothelial dependent [2]. The work by the Zhang et al. group demonstrated that intermedin promotes increases in blood flow through a neovascular network by increasing the size of the vascular lumen and reducing the number of excessive vascular sprouts. To generate intermedin-deficient mice using CRISP/Cas9, Wang et al. were able to exhibit that intermedin promotes increased vascular lumen size by stimulating the proliferation of confluent endothelial cells while preserving organized cell–cell contacts with no epochal changes in overall cell shape.

The vascular SMC responsiveness to mechanical stress and wall strain is a major morphogenic pathway in the vascular development, an important adaptive pathway in hypertension, and a pathogenic pathway in aneurysm formation. However, maladaptive responses to prolonged or aggravated stretch can also occur. A study conducted by Rodriguez et al. investigated the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoform-1 (Nox1) in maladaptive stretch-induced SMC phenotypes. They discovered that Nox1 expression in a myocyte enhancer factor 2B (Mef2B)-dependent manner was increased by cyclic stretch (10% at 1 Hz). Increases in Nox1 activity led to an increase in osteopontin expression and downregulated contractile phenotype markers calponin-1, smoothelin-B, and total actin fiber density [13]. Marfan syndrome is correlated with mutations in FBN1 (fibrillin 1), an extracellular matrix protein that plays a vital role as a component of microfibrils that help to configure Eln filaments in the walls of elastic arteries [14]. Fbn1 also directly binds the large latent transforming growth factor-beta (TGF-β) complex and bone morphogenetic proteins and impounds the growth factors in an inactive form [15] (Fig. 1.2).

Figure 1.2 Embryonic layers of artery and vein.

Genetic fate-mapping approaches have shown that arterial SMCs arise from multiple embryonic origins in vertebrate development [16]. Various SMC origins usually map on to different axial domains that underpin spatially to the anterior–posterior organization of the early embryo. The aortic root and ascending aorta are composed of SMCs that originate either from cardiac neural crest SMCs or from the second heart field (SHF–SMCs) [17]. A well-characterized Mef2c SHF enhancer-Cre mouse was used to reexamine the distribution of SHF–SMCs in the outflow tract and ascending aorta from 3 to 25 weeks of age [17]. This confirmed the previous findings and expanded them to show that the SHF-derived SMCs actually distribute from the aortic root along the outside of the developing aortic wall to form the outer medial layers of the ascending aorta. The overall organization and function of the epigenome are determined by the embryonic origin and lineage history of a