**2. Vascular system**

## **2.1. Cardiovascular system**

The cardiovascular system consists of three main components: heart, blood vessels (arteries, veins and capillaries) and blood. There are three types of anatomically and functionally distinct blood vessels: arteries, veins and capillaries. The arteries are primarily involved in the delivery of oxygenated blood and nutrients from the heart to target organs and tissues. They have thicker and more elastic vessel walls to complement the higher blood pressure for blood delivery from the heart. The veins carry deoxygenated blood, together with waste products and other factors secreted by the tissues back to the heart. They tend to have larger luminal areas and thinner vessel walls compared to the arteries, and have valves to complement the pressure changes. Connecting these two vessel systems are the capillaries that allow the direct exchanges of oxygen and nutrients with carbon dioxide and waste products between the target tissues and the blood. The walls of all vessels are generally composed of three layers: the tunica intima, tunica media and tunica adventitia. The innermost layer is formed by the tunica intima, which is made up of a single layer of ECs and connective tissues, both of which overlie the internal elastic lamina. The tunica intima has an important function as a selective permeable barrier between the extravascular space, the vascular wall and the blood. The tunica media forms the muscular element of blood vessels that resides between the tunica intima and the tunica adventitia, and comprises circumferentially arranged smooth muscle cells (SMCs) enclosed by a layer of external elastic lamina. They provide supports to the vessels and regulate blood flow and pressure via controlling the luminal diameter. The outermost layer, the tunica adventitia, is made up of connective tissues and matrix-secreting fibroblasts. It is critical to maintaining vascular structure and helps to anchor vessels in place to fit into the surrounding tissues. Capillaries constitute nonmuscular vessels and are only made up of an internal elastic lamina covered by a monolayer of ECs, and provide a huge surface area for exchanges of vital blood components and factors between vessels and tissues.

## **2.2. Endothelial cells and their impairments in CVDs**

Vascular endothelial cells (ECs) have a crucial and diverse role, arraying the innermost layer of the entire circulatory system. They act as the semi-selective and non-adherent barrier between the lumen of the vessels and the underlying tissues, regulating tissue perfusion and movement of inflammatory cells between them [6]. They are involved in regulating vascular permeability, blood flow, vascular tone and blood coagulation and are essentially involved in vascular remodelling in responses to diverse physiological and pathological stimuli. Physiologically, ECs exert anti-coagulant and anti-thrombotic effects through the secretion of anti-coagulant factors such as prostacyclin, nitric oxide (NO) and prostaglandin-E2 , and inhibit inflammatory cell adhesion in order to maintain vascular homeostasis [7]. Under pathological states, ECs are activated by vascular insults or pro-inflammatory cytokines, leading to increased permeability, encouraging extravasations of immune cells, which are followed by a series of pathological events leading to eventual vascular remodelling [7]. Decreased EC secretion of the potent vasodilator NO as a result of repressed activity of endothelial NO synthase (eNOS) also contributes to the circus of vascular pathogenesis [8]. These endothelial dysfunctions, whether environmental, genetic or a combination of both, critically contribute to the pathophysiology of many CVDs such as hypertension and atherosclerosis, and represent the discernible therapeutic targets for drug development [9].

## **3. Angiogenesis**

**1. Introduction**

hypertrophy.

therapies are in full swing.

**2. Vascular system**

**2.1. Cardiovascular system**

Cardiovascular diseases (CVDs) are a worldwide epidemic that have serious implication in public health and constitute a huge amount of healthcare expenditure. Although there are a number of preventable controllable risk factors, such as hypertension, hypercholesterolemia, smoking, obesity, lack of physical activity and diabetes, and others such as age, gender and family history are unmodifiable [1]. Progress in genetic sequencing has allowed the identification of numerous genetic variants associated with specific CVDs [2], but their mechanisms remain unclear. The last few years of research have been a key in understanding how epigenetic mechanisms such as histone modifications are involved in the occurrence and progression of CVDs including atherosclerosis, heart failure, myocardial infarction and cardiac

Epigenetics represent a phenomenon of altered heritable gene expression without changes to the underlying DNA sequences. The epigenetic alterations can be affected by exogenous stimuli such as diabetes milieu, diets and smoking, while at other times these alterations can subsequently trigger disease initiation [3]. Thus, the impact of epigenetics in CVD is now emerging as an important regulatory key player at different levels from pathophysiology to therapeutics. For instance, histone alterations have been implicated in ECs response to hypoxia and shear stress, in angiogenesis and in endogenous recovery following myocardial infarction (MI) [4]. On the other hand, HDAC inhibitors (HDACi) have been investigated for

Tissue repair is one of the main therapeutic challenges facing the scientific community. There are various approaches in improving tissue recovery depending on the pathological conditions, but most of these conditions are initiated by local ischaemia and require a rich network of blood supply for tissue regeneration. Hence, angiogenesis plays a vital part in tissue regeneration in the treatment of CVDs. At present, the promising potentials of angiogenesis

The cardiovascular system consists of three main components: heart, blood vessels (arteries, veins and capillaries) and blood. There are three types of anatomically and functionally distinct blood vessels: arteries, veins and capillaries. The arteries are primarily involved in the delivery of oxygenated blood and nutrients from the heart to target organs and tissues. They have thicker and more elastic vessel walls to complement the higher blood pressure for blood delivery from the heart. The veins carry deoxygenated blood, together with waste products and other factors secreted by the tissues back to the heart. They tend to have larger luminal areas and thinner vessel walls compared to the arteries, and have valves to complement the pressure changes. Connecting these two vessel systems are the capillaries that allow the direct exchanges of oxygen and nutrients with carbon dioxide and waste

potential protective effects in heart muscles during acute MI [4, 5].

150 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

There are three main processes that contribute to the formation of new blood vessels that are termed globally as neovascularisation:

– Vasculogenesis is defined as the de novo formation of vascular structures by the migration of stem cells to the site of vascularisation and differentiation into ECs. Although it was originally thought to be exclusive to embryonic development, it is now widely accepted that the process can also take place in adults, which opens up a new avenue for clinical applications [10].


Angiogenesis is a very complex process that can be simplified into three categories: mechanical, chemical and molecular factors (see Ref. [12] for a more extensive review).

