Artery

1.7.1 Normal Function

Arteries are muscular and elastic tubes that transport blood under a high pressure exerted by the pumping action of the heart. By contraction (systole) and relaxation (diastole) of the heart vascular cells change the luminal diameter, which allows blood vessels to maintain a pulse pressure to transform a pulsating blood flow into a continuous flow for the peripheral tissue. During diastole, the pulse reflection allows a flow-back into the coronary arteries. Systemic arteries carry blood from the heart through the smaller arterioles and capillaries to the rest of the body, whereas pulmonary arteries carry blood from the heart to the lungs.

Arteries are composed of three main layers: external layer of connective tissue and elastic membrane called tunica adventitia, followed by the layer of SMCs – tunica media and internally located monolayer of endothelial cells resting on connective tissue and internal elastic membrane – tunica intima (Figure 1.11A).

Figure 1.11: Cross-section of normal artery and schematic representation of vascular smooth muscle cell (VSMC) phenotypes present in the media. (A) Schematic representation of the layers of artery. (B) Different phenotypes of VSMC present in the media.

Systemic arteries are divided into two main types – muscular, which tend to be larger (>10 mm in diameter), and elastic, which tend to be smaller (0.1 – 10 mm in diameter) with corresponding differences in the proportion of these layers. Aorta, for instance is the main systemic artery, which is connected directly to the heart (approximately 30 mm in diameter) (Hager et al. 2002) It acts as an elastic buffering chamber behind the heart, modulating wall elasticity to regulate compliance (the Windkessel function) (Belz 1995). It branches out to form coronary arteries, which branch further out into the brachiocephalic artery, left common carotid and the left subcalvian arteries. Renal arteries (arteria renalis) are muscular and branch out of the abdominal aorta and have diameter of about 25 mm (Turba et al. 2009). The role of muscular arteries and arterioles is to regulate the blood reflection, distribution and conductance.

1.7.1.1 Structural Components of the Artery and Their Role in Adaptation, Protection and Repair

1.7.1.1.1 Endothelium

Since endothelium is the most inner layer of the artery, it is submitted to continuous shearing forces of the circulating blood. It also is in constant contact with circulating cells and plasma components. Endothelial cells are smooth and elongated, contain myofibrils and renew every 2-6 years (Tedgui 1999). Their luminal surface is coated with glycoprotein coat forming glycocalix responsible for the anti-thrombogenic properties of this surface. ABO antigens, factor VIII antigen, and many others give endothelial cells distinctive immunologic characteristics (Tedgui 1999). Endothelial cells are packed tightly, connected by tight junctions forming zona occludens, which provides a tight seal, allowing 1-10% of luminal protein to penetrate into the wall

(Simionescu et al. 1976, Tedgui 1999). The movement of a material from the lumen into the vessel wall occurs via abundant pynocitic vesicles.

1.7.1.1.2 Tunica Media and Smooth Muscle Cells

The function of the medial layer of the artery is generation of force for vasoconstriction. This is due to the presence of thick layer of SMCs, embedded in the mesh of basal lamina and collagen fibrils, tied to a system of elastic fibrils. Factors that influence contraction and relaxation of SMCs are G protein-coupled receptors’ modulators, pressure, tension, agents acting on ion channels or signalling systems, growth factors and extracellular matrix components, cell adhesion molecules and integrins (Hunt 2002).

There are many different phenotypes of VSMC, with contractile and synthetic representing two most distinct morphologies. Interestingly, the vastness of phenotypes translates into the diversity of functions (Figure 1.11B). What is more, VSMCs have a remarkable capacity to switch between phenotypes, also referred to as ‘phenotypic modulation’ (Hao et al. 2003). The main purpose of such biological plasticity is adaptation and repair. The contraction of VSMCs is involuntary and is regulated by the cytosolic calcium concentration, as well as the sensitivity of calcium of the contractile elements reacting to changes in the cell-surrounding environment. The contractile state is maintained by binding of hormones, neurotransmitters such as adrenaline and other auto/paracrine chemical signals to their receptors on the cell. The contraction then involves calcium influx to the cell, which is exerted via multiple mechanisms. The next step involves calmodulin binding and activation of myosin light chain kinase (MLCK), with calmodulin-MLCK complex catalysing phosphorylation of myosin light chains enabling actin-myosin interaction and force

generation. -actin is one of the most abundant proteins of the VSMC cytoskeleton, hence why it is often used as an endogenous indicator of phenotype (Hunt 2002). Healthy contractile phenotype of VSMCs is characterised by abundant proteins involved in the process of contraction, such as -actin, desmin and vimentin. Also cell morphology has a characteristic elongated, spindle like shape. During transition to secretory phenotype cells become more rounded and irregular in shape. Progressive changes in the cytoskeleton result in reduction of -actin and expression of specific transcription factors. Secretory phenotype is a response to adaptation and/or repair – cells are capable of releasing matrix vesicles containing minerals or other unwanted compounds into the ECM in order to maintain intracellular homeostasis (Thyberg et al. 1997).

1.7.1.1.3 Adventitia

The cells of the adventitia are sparse and the majority are fibroblasts. The supply of oxygen and nutrients to adventitia and media is facilitated by a network of microvasculature - vasa vasorum (present only in larger arteries) (Heistad et al.

1981). Adventitia also contains nerves, which regulate SMCs function; lymphatic network and perivascular connective tissue. Pericytes have enormous differentiation capabilities and depending on the need they can become fibroblasts, SMCs or macrophages. They are important in angiogenesis and have been implicated in the regulation of the blood flow (Peppiatt et al. 2006).

1.7.2 Normal Regulation

Arteries have a natural capacity to regulate lumen diameter in response to changes in the blood flow. Vascular endothelium plays an important role in regulation of

vascular homeostasis. One of essential functions of the endothelium is the synthesis and release of the vasodilator nitric oxide (NO) (Ignarro et al. 1987). NO is synthesized from the amino acid substrate L-arginine by the enzyme endothelial nitric oxide synthase (eNOS) (Palmer et al. 1988). In response to mechanical shear stress or binding of acetylcholine or bradykinin to their receptors, NO diffuses through the basal membrane to SMCs, where it initiates conversion of GTP to cyclic GMP through soluble guanylyl cyclase orchestrating VSMC relaxation, vasodilation, proliferation and permeability (Moncada 1993, Scott-Burden et al. 1993).

1.7.3 Pathological Processes

Chronic stress on vasculature can be caused by diabetes, smoking, infection, CKD. In principle, it can be divided into localised (effect of which may be atherosclerosis – formation of atheroma, localised fat and cholesterol containing plaque in the intimal layer of the artery) and systemic (arteriosclerosis – loss of elasticity and consequently hardening of the arteries due to prolonged blood overload occurs typically in old age).

Both atherosclerotic and arteriosclerotic changes may lead to calcification. Progression of intimal calcification can result in plaque dislodgement causing myocardial infarction, i.e. downstream occlusion of the artery. Small areas of calcifications with sparse calcium phosphate crystals seem to be more bioactive than larger calcification plaques, resulting in triggering an inflammatory response and eventually cell death (Ewence et al. 2008)

Eutrophic inward remodelling is the physiological response to raised blood pressure. However, if the high blood pressure overpowers arteries’ ability to autoregulate, then a blood vessel, which is exposed to high stress, switches to replace eutrophic inward

remodelling with hypertrophy. Important modulators of tissue remodelling are matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). MMPs are collagenases with the ability to degrade polymerised, supramolecular collagen, that has been organised into fibrils (type I, II, III).