All blood vessels of the circulatory system are lined with endothelium. Endothelial cells form a 0.2-0.4 µm thick monolayer that is in direct contact with the blood. Together the endothelial cells weight ∼1 kg. Large blood vessels, arteries and veins, have layers of smooth muscle and connective tissue (basement membrane) behind the endothelium; thickness of basement membrane depends on the local blood pressure. Basement membrane of capillaries contains type IV collagen and laminin, while in arterioles it is mainly composed of type I collagen and elastin. Endothelial cells are anchored to the basement membrane by integrins. The walls of veins are thinner and less elastic than arteries, containing less smooth muscle and more connective tissue. Perivascular cells (or mural cells) include the smooth muscle cells and pericytes, and are derived from different cell lineages in different organs (Sweeney & Foldes, 2018). Capillary walls do not usually contain smooth muscle cells. Precapillary smooth muscle cells can wrap up to three times around the endothelium.
Capillary 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. Capillaries in most of the skin are continuous, but fenestrated capillaries are found for instance in fingers. In the spleen, liver, and bone marrow the endothelium is very permeable due to large openings between endothelial cells (“sinusoidal vessels”). The tightness of endothelial cell junctions affects the paracellular permeability, but endothelial cells transport many compounds by endocytosis and exocytosis (transcellular or transcytotic transport), which are tightly regulated processes (Komarova & Malik, 2010; Park-Windholl & D’Amore, 2016).
Glycocalyx is a negatively charged 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. Glycocalyx covers the endothelial cells, thus regulating the access of substrates from blood to the transcellular transport, but it also covers the fenestrations between endothelial cells, thus regulating the paracellular permeability, too. Diaphragms are the organized glycoprotein structures which fill the fenestrae. Glycocalyx also mediates the shear stress, and limits the adhesion of blood cells, including white blood cells, and proteins to endothelial wall. Heparin sulphate glycosaminoglycans (GAGs) prevent blood coagulation.
Vascular endothelial growth factor (VEGF) proteins are key regulators of endothelial permeability, among many other functions, especially related to tissue growth and remodelling, including angiogenesis and lymphangiogenesis. VEGF family comprises of several ligands, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor (PGF). VEGFs are additionally spliced into several isoforms. VEGFs bind to tyrosine kinase receptors (VEGFRs), of which VEGFR2 is directly involved in regulation of vascular permeability (Olsson et al., 2006). VEGFs may have different effects depending on they bind to endothelial cells from luminal or abluminal side (Hudson et al., 2014). Tissue hypoxia is the main driver for production of VEGFs.
Endoglin (CD105) is a transmembrane glycoprotein that works as an adhesion molecule in endothelial cells via its RGD motif, and as a co-receptor for several ligands of the transforming growth factor beta (TGF-β) cytokine family (Rossi et al., 2019). Endoglin is induced in hypoxia and involved, with VEGFR2, in angiogenesis. PET tracers targeting endoglin, mainly labelled antibodies, have been developed (Hong et al., 2014; Hendrikx et al., 2016). TGF-βs are involved in tissue remodelling and fibrosis (Biernacka et al., 2011; Dobaczewski et al., 2011). TGF-βs, especially TGF-β2, are immune suppressors, involved in development of immune tolerance. 89Zr-labelled fresolimumab, that binds TGF-β, has been used in tumour imaging.
Sphingosine-1-phosphate (S1P), when bound to S1P1 receptor, promotes the integrity of endothelial cells and their junctions. Activation of S1P2Rs on endothelial cells results in disruption of junctions, increasing paracellular permeability.
Pericytes are located outside or inside of the basement membrane of precapillary arterioles and postcapillary venules, that interact directly and via paracrine factors with the endothelial cells on the inner side of the basement membrane. Pericytes have a role in angiogenesis, inflammation, production of extracellular matrix (ECM), and fibrosis. Pericytes can change the composition of ECM, and thus regulate its permeability (Goddard & Iruela-Arispe, 2013).
Pericytes have minimal cytoplasm and project finger-like structures around the capillaries and through basal membrane, but their precise morphology and function is variable. Precapillary pericytes are contractile, and contraction of a single pericyte can arrest blood flow into a capillary (Borysova et al., 2013). Capillary pericytes can respond to metabolic stimuli from surrounding tissue and generate and conduct membrane depolarization to precapillary arterioles and postcapillary venules (Hashitani et al., 2018). Pericytes at the postcapillary venules regulate the entry of white blood cells into the tissue (Proebstl et al., 2012). In the brain, pericytes are important for the formation of blood vessels, maintenance of the blood-brain barrier, and control of perfusion (Dalkara & Alarcon-Martinez, 2015).
Vascular endothelium and tissue surrounding the blood vessel secretes paracrines, including prostaglandins, which cause contraction or relaxation of the pericytes around the capillaries, reducing or increasing capillary diameter and blood flow. In contrast to the classical view, much of the blood flow increase is generated by dilation of capillaries, rather than of arterioles which dilate more slowly (Attwell et al., 2016). Local autoregulation stabilizes perfusion when arterial pressure changes. Autoregulation is prominent in the brain (Peppiatt et al., 2006; Hall et al., 2014), where pericytes are abundant, and in kidneys, but occurs in most vascular beds. Additionally, vasoactive metabolic end-products can induce changes in tissue perfusion. 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) and endothelial cells. 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.
Juxtaglomerular cells in the kidneys are modified pericytes in the glomerular capillary, which regulate the renal perfusion and glomerular filtration rate. Pericytes are numerous also on descending vasa recta in the renal outer medulla, regulating medullary blood flow (Kennedy-Lydon et al., 2013). Detachment of pericytes from endothelial cells may be a key event leading to loss of peritubular capillaries (rarefaction) in development of chronic kidney disease.
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. Endothelial cells modulate vascular tone by producing or processing vasodilators (NO, PGI2, H2S, bradykinin, histamine, serotonin, substance P) and vasoconstrictors (ET-1, TxA2, angiotensin II, ROS). Production of NO and PGI2, and degradation of extracellular ATP, inhibits platelet activation.
Endothelial dysfunction is an altered response of endothelial cells to various regulatory stimuli (Deanfield et al., 2007). Reduced production of NO, impaired fibrinolytic activity activity, enhanced expression of adhesion molecules and inflammatory mediators, increased production of ROS, and increased permeability of endothelial barrier are the hallmarks of endothelial dysfunction. Endothelial function is often measured by flow-mediated dilation (FMD); increased blood flow leads to increased shear stress, and endothelium-dependent response to that is relaxation of a conduit artery, usually measured as reactivity of the brachial artery using ultrasonography (Widlansky & Malik, 2015).
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 altered. 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. Abnormal angiogenesis causes formation of new leaky vessels, which is common in tumours. Pulmonary diseases, including asthma and acute lung injury, are associated with pulmonary oedema, caused by increased endothelial permeability.
- Vascular system
- Blood-brain barrier
- Vascular volume fraction
- Input function
- Perfusion (blood flow)
- Inflammation and infection
- Wound healing
- Lymphatic system
Aranda-Espinoza H (ed.): Mechanobiology of the Endothelium. CRC Press, 2015. ISBN 9781482207248.
Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, Pollock DM, Webb DJ, Maguire JJ. Endothelin. Pharmacol Rev. 2016; 68(2): 357-418. doi: 10.1124/pr.115.011833.
Eelen G, de Zeeuw P, Treps L, Harjes U, Wong BW, Carmeliet P. Endothelial cell metabolism. Phys Rev. 2018; 98: 3-58. doi: 10.1152/physrev.00001.2017.
Goddard LM, Iruela-Arispe ML. Cellular and molecular regulation of vascular permeability. Thromb Haemost. 2013; 109(3): 407-415. doi: 10.1160/TH12-09-0678.
Leahy MJ (ed.): Microcirculation Imaging. Wiley-Blackwell, 2012. doi: 10.1002/9783527651238.
Ono S, Egawa G, Kabashima K. Regulation of blood vascular permeability in the skin. Inflamm Regen. 2017; 37:11. doi: 10.1186/s41232-017-0042-9.
Park-Windholl C, D’Amore PA. Disorders of vascular permeability. Annu Rev pathol Mech Dis. 2016; 11: 251-281. doi: 10.1146/annurev-pathol-012615-044506.
Peters AM, Jamar F. The importance of endothelium and interstitial fluid in nuclear medicine. Eur J Nucl Med. 1998; 25(7): 801-815. doi: 10.1007/s002590050286.
Scallan J, Huxley VH, Korthuis RJ. Capillary Fluid Exchange - Regulation, Functions, and Pathology. Morgan & Claypool Life Sciences, 2010. doi: 10.4199/C00006ED1V01Y201002ISP003. NCBI Bookshelf: NBK53447.
Thiriet M. Anatomy and Physiology of the Circulatory and Ventilatory Systems. Springer, 2014. doi: 10.1007/978-1-4614-9469-0.
Tuma RF, Durán WN, Ley K (eds.): Microcirculation. 2nd ed., Elsevier, 2008. ISBN: 978-0-12-374530-9.
Updated at: 2019-01-30
Created at: 2016-05-15
Written by: Vesa Oikonen