Vascular system (Fig 1) consists of pulmonary and systemic circulation. Blood is pumped from the right ventricle (RV) of the heart into the lungs. Oxygenated blood flows from the lungs into the left atrium (LA) and then into the left ventricle (LV) of the heart, from where it is pumped into the arteries of the systemic circulation. From body organs the blood flows via the veins into the right atrium (RA) of the heart. Veins from the upper part of the body join to form the superior vena cava, veins from the lower part of body form inferior vena cava, and veins from the heart join into coronary vein, all of which empty into the RA. At rest the veins contain <60% of the blood, most in venules.
All blood vessels are lined with endothelium. Behind the endothelium, arteries and veins have layers of smooth muscle and connective tissue (basement membrane); thickness depends on the local blood pressure. The smooth muscle is normally contracted partially (muscle tone), but can be contracted more (vasoconstriction) or become relaxed (vasodilation). Homeostatic reflexes lead to vasodilation in organs that have increased need for oxygen or CO2 removal, with subsequent vasoconstriction in other organs. Arterioles may consume a significant proportion of the oxygen used by the body at rest (Tsai et al., 2003).
Vascular walls are under constant stretch and shear stress because of the pulsatile blood pressure and flow. The elastic walls of arteries store the energy of myocardial ventricular ejection during the systole, and release it during the diastole. This keeps up the blood pressure and flow in the arteries and arterioles even during systole. The pulsatile change of arterial blood volume, and non-pulsatile flow of venous blood in periphery, enables assessment of arterial oxygen saturation (SaO2) using conventional pulse oximeter sensors.
The walls of veins are thinner and less elastic than arteries, containing less smooth muscle and more connective tissue. Capillary walls do not usually contain smooth muscle cells.
Glycocalyx is a glycoprotein layer on the inner side of the blood vessel. The permeability of glycocalyx is different for each substrate, based on the molecule size and charge. It also mediates the shear stress, and limits the adhesion of blood cells to endothelial wall.
Endothelium is continuous in skeletal muscle, heart, lungs, and especially tight in the brain (blood-brain barrier). Fenestrated, well-permeable endothelium is found in for example pancreas and intestine. In the spleen, liver, and bone marrow the endothelium is very permeable due to large openings. The surface area of capillaries can be increased via angiogenesis. In addition to its physical properties, endothelium regulates the transport of many compounds by endocytosis and exocytosis.
Pericytes are located outside or inside of the basement membrane, but interact directly and via paracrine factors with the endothelial cells on the inner side of the membrane. Pericytes have minimal cytoplasm and project finger-like structures around the capillaries and through basal membrane. Pericytes have a role in angiogenesis, inflammation, production of extracellular matrix, and fibrosis.
In humans, at rest, cardiac output (CO) is about 5-6 L/min, which is directed into the liver and digestive tract (1.35 L/min), skeletal muscle (1.05 L/min), kidneys (1.0 L/min), brain (0.7 L/min), skin (0.25 L/min), heart (0.20 L/min), and other tissues (about 0.5 L/min). Most of the blood flow to the liver enters via the portal vein from the splanchnic circulation (mostly from the gut and spleen), and ∼0.3 L/min directly from the hepatic artery.
During maximal cycle ergometry, nearly 85% of total blood flow is directed to the working legs.
Control of arterial diameter
Blood flow in the microcirculation is controlled by vasoconstriction and vasodilation, based on the local oxygen concentration and shear stress, mediated by nitric oxide (NO) signalling. The rhythmic oscillation of small artery and arteriole diameter is called vasomotion. Vasomotion is commonly studied in skin because the skin vasculature is easily accessible to several measurement techniques.
Flow fluctuation (flowmotion) in muscle is affected by vasomotion for myogenic (about 0.1 Hz), neurogenic (about 0.04 Hz), and endothelial (about 0.01 Hz) activity; heart rate and respiration cause flow additional fluctuations.
Sympathetic neurons release noradrenaline (norepinephrine) which binds to the α-adrenergic receptors on vascular smooth muscle cells. Increased release of norepinephrine leads to increased contraction of the smooth muscle and thus constriction of the arterioles.
Local autoregulation stabilizes perfusion when arterial pressure changes. Autoregulation is prominent in the brain and kidneys, but occurs in most vascular beds. Additionally, vasoactive metabolic end-products can induce changes in tissue perfusion.
Vascular endothelium and tissue surrounding the blood vessel secretes paracrines, including prostaglandins, which cause contraction or relaxation of the vascular smooth muscle, pericytes, around the capillaries. Blood erythrocytes participate in the control with haemoglobin working as a O2 sensor. Shear stress in capillaries activates NO synthase in erythrocytes (Ulker et al., 2011). Part of haemoglobin in erythrocytes is localized to the plasma membrane, supporting rapid transfer of NO and other substrates. NO-containing haemoglobin (usually <1%) shows O2 kinetics similar to myoglobin.
Hyperemia (increased organ blood flow) can be caused by increased metabolism, or as a response to brief ischemia (reactive hyperemia).
Alterations in microcirculation are common in critically ill patients. Microvascular density, or the proportion of perfused capillaries, can be decreased, leading to increased heterogeneity of tissue perfusion. Reduced NO production or increased NO breakdown leads to impaired regulation of vasodilation.
Even in normal skeletal muscle or adipose tissue the interstitial concentrations of many substrates, such as glucose and amino acids, and hormones, such as insulin, are substantially lower than in plasma, suggesting that transendothelial transport is a limiting factor. In endothelial dysfunction the transport barrier may be substantially increased. Dysfunction of endothelial barrier is found for example in hypertension, cigarette smoking, inflammation, and diabetes (or metabolic syndrome).
In capillary leak syndrome an increase in capillary permeability to proteins leads to oedema and hypotension, and often acute kidney injury (Siddall et al., 2017). It is commonly associated with sepsis, but can result from other diseases, including autoimmune diseases.
Blood pressure is controlled by autonomic nervous system reflexes that regulate both cardiac output and peripheral resistance. Central nervous system maintains balance between sympathetic nervous system innervating the blood vessel walls and heart, and vagus nerve innervating the heart (Dampney, 2016). Renin-angiotensin-aldosterone system (RAAS) regulates plasma [Na+]. Neuropeptide apelin enhances sympathetic nervous system activity and increases blood pressure. The same neurons that express apelin also express vasopressin, which affects stress response, and is an important regulator of kidney function.
The kidney regulates extracellular fluid volumes by excreting water and Na+; kidney responds to increased renal perfusion pressure by increasing the water and Na+ excretion (“pressure natriuresis”). Kidney serves also as an oxygen sensor, and responds to systemic hypoxia by releasing erythropoietin and possibly by increasing blood pressure.
Hypertension (HTN) affects over 1 billion people, and poorly managed HTN is associated with strokes, coronary artery disease, and chronic kidney disease. Consistent HTN leads to higher threshold for pressure natriuresis, and renal transplantation studies have shown that transplants from hypertensive rats leads to HTN in normotensive rats, and vice versa.
Narrowing of arteries, usually due to atherosclerosis, is called cerebrovascular disease (CVD), when it affects the arteries that supply the brain, coronary artery disease (CAD), when it affects the heart, and peripheral arterial disease (PAD), when it affects other arteries. Atherosclerosis is often linked to more than one of these diseases. Peripheral vascular disease (PVD) includes PAD and chronic venous disease.
Cerebral perfusion reserve in CVD can be assessed with radiowater PET at baseline and after acetazolamide challenge. Ischemia- and reperfusion-induced apoptosis has been of interest especially in CVD imaging. TSPO imaging has been used to monitor the neuroinflammation following stroke.
Chronic venous disease (CVeD) is very common, especially in the lower limbs. It includes deep vein thrombosis and chronic venous insufficiency (CVI, also known as post-thrombotic syndrome). The walls of varicose veins are heterogeneous, with sections of hypertrophy and atrophy, and abnormal and overexpressed ECM components (Jacobs et al., 2017). Valvular incompetence leads to reflux, venous hypertension, increased capillary pressure, and further to accumulation of fluid within interstitial space (oedema). Lymphatic drainage fails in the advanced stages of the disease. Normal fluid shear stress is absent in dilated vessels. Increased vessel permeability leads also to extravasation of white blood cells and plasma proteins into the tissue. Accumulation of fibrin around the capillaries (“fibrin cuffs”) may lead to venous ulceration and lipodermatosclerosis. Increased perfusion and reduced OEF was seen skin and subcutaneous tissue in venous ulceration and liposclerosis using PET (Hopkins et al., 1983; Spinks et al., 1985).
Deep vein thrombosis (DVT), is the formation of a blood clot within deep vein, most commonly in the legs, pelvis, and in the abdomen. Detached clot will travel to the lungs where it will clog the pulmonary arteries leading to pulmonary embolism. DVT often develops in the valves of calf vein, from where it can move and grow via the vein, or dissolve into the blood (fibrinolysis). Local low oxygen concentration (hypoxemia) in the venous blood can induce the clot formation.
Thrombosis has several molecular targets that could be used in diagnostic imaging. Thrombi contain red blood cells and platelets. Fibrin is present in all thrombi but not in circulating blood. Several fibrin-targeted tracers have been developed (Ciesienski et al., 2013; Oliveira et al., 2015; Blasi et al., 2015). Tissue factor (TF) is a transmembrane glycoprotein which, when combined with factor VII, starts the cascade leading to generation of thrombin and fibrin network. TF is also overexpressed in many tumour cells, promoting angiogenesis and tumour growth. [18F]ASIS, [18F]FVIIai, and [64Cu]NOTA-FVIIai are active-site inhibited factor VII analogues, which have shown promise in imaging TF expression level (Erlandsson et al., 2015; Nielsen et al., 2016a and 2016b).
Glycoprotein IIb/IIIa receptor is a member of integrin family, also known as αIIbβ3; when activated by platelets, it binds blood fibrinogen motifs with RGD motif, resulting in cross-linking and growing of thrombus. [18F]GP1 is a promising radioligand for thrombus PET imaging (Lohrke et al., 2017).
Inflammation is factor many vascular diseases, including atherosclerosis (Teague et al., 2017). Atheroma is an accumulated mass (plaque) in the inner layer of arterial wall, consisting mostly of living and dead macrophages, lipids, calcium, and fibrous components of extracellular matrix. The plaque may narrow the artery, restricting the blood flow to the tissue that the artery is feeding. Ruptured plaques leak their contents, including cholesterol crystals, that cause inflammation and injury in other tissues. PET tracers that have been used to study atheromas include [18F]NaF, [18F]FLT, and [18F]choline (Teague et al., 2017).
- Vascular volume fraction
- Input function
- Perfusion (blood flow)
- Cardiac PET imaging
- Renal PET imaging
- Inflammation and infection
- Apoptosis and necrosis
- Wound healing
- Lymphatic system
- Instructions by tracer
- Tracer administration
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Created at: 2016-05-15
Updated at: 2018-09-25
Written by: Vesa Oikonen