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.
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), myocardial muscle (0.20 L/min), and other tissues (about 0.5 L/min). The lungs receive 101-105% of cardiac output, because lungs have have two circulations, pulmonary (part of vascular system) and bronchial circulation (part of systemic circulation). Also liver has dual blood supply: 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 exercise CO increases and blood flow is redistributed away from inactive vascular beds toward exercising muscles ("vascular shunt mechanism"). Vigorous exercise can increase CO to 25 L/min, of which ∼1 L/min is directed into the liver and digestive tract, ∼20 L/min into skeletal muscle, ∼0.75 L/min into the kidneys, ∼0.8 L/min into the brain, ∼0.25-0.5 L/min into skin (depending on the need for thermoregulation), ∼1 L/min into myocardial muscle. During maximal cycle ergometry, nearly 85% of total blood flow is directed to the working legs. These effects may lead to shortening of the mean circulation time (Sowton et al., 1968). Marked fraction of white blood cells, platelets, and red blood cells are stored in the spleen, from where those can be rapidly released, increasing blood cells counts and haematocrit.
Heat and cold stress increases the activity of sympathetic system and blood levels of catecholamines, providing adrenergic stimulus to organs. The splanchnic blood flow can decrease even to one fifth of the baseline, and renal blood flow can drop 15-30% (Wilson, 2017). Even just mental stress reduced cortical renal blood flow by ∼30% (Middlekauff et al., 1997). Skin is thin and contains only microcirculatory network, but still contains normally >9% of the total blood mass. Skin has important role in thermoregulation and haemodynamics, and the blood flow to skin can vary between 0.02 and ∼7 L/min (Agache et al., 2017).
Circulation is a closed system, and an indicator bolus administered to a certain point of the circulatory system will reappear at the same point after some time. (Re)circulation time is the transit time of the bolus through the circulatory system, and it has often been measured from pulmonary artery, aorta, or from lungs using indicator gases (Schröder et al., 1992; Morris et al., 2007). The first portion of the indicator to recirculate has passed through a well-vascularized system close to the heart, such as the coronary, bronchial, thyroid, and renal systems (Sowton et al., 1968). Coronary mean transit time is 8±2 s at rest, but dye appearance time and peak times were markedly shorter, 3.8±1.2 s and 4.7±1.8 s, respectively (Ishikawa et al., 1974). The mean blood circulation time through kidneys was 5.2 s, while the fastest renal circulation time for red blood cells was 2.0-3.9 s and for plasma 2.1-4.8 s (Ladefoged & Pedersen, 1967).
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 parasympathetic nervous system (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. Renovascular diseases such as ARAS lead to secondary HTN (Herrmann & Textor, 2018). HTN, congestive heart failure, and diabetic nephropathy are commonly treated by inhibiting RAAS. Consistent HTN (hypertonia) leads to higher threshold for pressure natriuresis. Renal transplantation studies have shown that transplants from hypertensive rats leads to HTN in normotensive rats, and vice versa. Renal sympathetic denervation has been used to reduce blood pressure.
Dahl salt-sensitive rats are a genetic model of sodium-induced hypertension. Diet with high Na-content leads to decreased blood flow and increased ROS production in the medulla of kidneys, and progressive hypertension, leading to end-stage renal disease.
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. The surface area of capillaries can be increased via angiogenesis.
Microcirculation comprises vessels with diameter <200 µm (other commonly used limits are <100 µm and <150 µm), including arterioles, blood capillaries (diameter 5-8 µm), venules, and lymphatic capillaries and collectors. Microcirculation supplies tissues with nutrients and oxygen, and removes catabolites and CO2; supplies and distributes hormones; regulates tissue temperature; and controls tissue fluid balance and blood pressure.
Perfusion is expressed as a volume of blood entering and exiting a volume of tissue per unit time. 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 endothelium modulates vascular tone by balancing production of vasoconstrictors and vasodilators. 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. In the skin arterioles, vasomotion consists of two waves with different frequency: neurogenic at 0.1-0.2 Hz, and myogenic at 0.02-0.03 Hz; these are superimposed on the heartbeat and respiratory vasoconstriction (Agache et al., 2017). 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.
Alterations in microcirculation are common in critically ill patients, related to dysfunction of endothelial barrier.
Sympathetic neurons release noradrenaline (norepinephrine) which binds to the α-adrenergic receptors on vascular smooth muscle cells. Increased release of noradrenaline 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 capillary secretes paracrines which cause contraction or relaxation of the pericytes around the capillaries. Hyperemia (increased organ blood flow) can be caused by increased metabolism, or as a response to brief ischemia (reactive hyperemia).
NO is produced by endothelial cells from L-arginine in a reaction catalyzed by NO synthase (eNOS). Released NO causes increased cGMP production in smooth muscle cells surrounding arterioles. Shear stress and pulsatile stretching activate NO production. H2S, another vasodilator, is produced by both endothelial and smooth muscle cells. Endothelial cells produce vasoconstrictors such as endothelin-1. On surface of endothelial cells, angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II, which is a potent vasoconstrictor (Widlansky & Malik, 2015).
Prolonged changes in the demand for oxygen or other substrates leads to vascular remodelling via angiogenesis and angiolysis. Angiotensin II- and HIF-1/VEGF-pathways are involved in the regulation of these prolonged changes in microcirculation.
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.
Endothelial cells regulate the activity of platelets and fibrinolytic system, and local inflammatory processes (Pate et al., 2010). Endothelial cells keep phosphatidylserine in the inner leaflet of their plasma membrane, depriving the clotting factors of a surface that is required for their assembly.
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 (PE). 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.
Thromboembolism has several molecular targets that could be used in diagnostic imaging. Thrombi contain red blood cells and platelets. For instance, integrin αIIbβ3 (glycoprotein IIb/IIIa receptor) targeting [18F]GP1 detected thromboembolic foci in all patients with DVT or PE, and increased uptake in many vessels that were not detected by conventional imaging (Lohrke et al., 2017; Kim et al., 2019).
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).
- Lymphatic system
- Endothelial barrier
- Cardiac PET imaging
- Cardiac output and stroke volume
- Cardiopulmonary transit time
- Renin-angiotensin-aldosterone system (RAAS)
- Apoptosis and necrosis
- Wound healing
- RBCs, WBCs, and platelets
- Tracer administration
- Vascular volume fraction
- Input function
- Perfusion (blood flow)
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Updated at: 2021-12-23
Created at: 2016-05-15
Written by: Vesa Oikonen