The vascular endothelium: structure and function

Vascular endothelial cells
The complex structure–function relationship of vascular endothelial cells has fascinated pathologists, physiologists, protein chemists and scientists for centuries. The structural aspects of endothelial cells are themselves deceivingly simple and divided into three distinct surfaces: the luminal surface (non-thrombogenic), the cohesive junctional surface and an adhesive abluminal surface (reviewed in Tucker) [4]. The functional roles and broad-reaching intricacies of each surface are highly complex and, in many ways, distinguish normal physiology from pathological conditions [5].
The vascular endothelium’s functional role is separated into distinct parts: (1) barrier function—highly selective and regulates inflammatory and immune responses, (2) transport function—responsible for cell–cell signaling and pinocytosis (i.e. particles in extracellular fluid enter the cell through invaginations or clefts in the cell membrane), (3) vascular repair function-restores structural and functional normalcy, (4) angiogenesis function-reparative and adaptive to injurious conditions, (5) thromboregulation function- supports physiological blood flow and prevents unwanted (or needed) blood clotting, (6) vasoregulation function—responds to local conditions and signals vasodilation or vasoconstriction, (7) metabolic function—responsible for a highly regulated synthesis of growth factors, adhesion molecules and receptors; and (8) immune function-responds to a variety of immune cells, expresses histocompatibility antigens and regulates antigen presenting cells [6] (Fig. 3).
Fig. 3 Endothelial cells exhibit a broad range of functions that include physical barrier, endocrine, paracrine and autocrine, vascular remodeling and repair, regulation of thrombosis, regulation of inflammation, cell migration and cellular signaling. Endothelial cell (EC), nitric oxide (NO), prostacyclin (PGI2), endothelin (ET), tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI)-1, inter-cellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, platelet/endothelial cell adhesion molecule (PECAM)-1
The vascular endothelium constitutes an inner lining of arteries, veins and capillaries. Accordingly, it is in direct communication with circulating blood components and tissues (reviewed in Krüger-Genge) [7]. In addition to its fundamental substrate delivery capabilities, the vascular endothelium is an active endocrine and paracrine organ. Moreover, it is tissue-specific, carrying out specialized functions as needed under highly dynamic conditions.
Even a brief summary of vascular endothelium structure and function underscores its critical role in human health and disease, and the potential consequences of injury and resulting dysfunction. These include, but are not limited to, vascular integrity, permeability, cellular/tissue cross talk, and the regulation of vasomotor activity, coagulation and inflammation [7, 8].

Microvascular endothelial cells
The microcirculation is represented by blood vessels of the smallest diameter (terminal arterioles, capillaries, and venules), but overall greatest surface area. In addition, the microcirculation plays a critical role in tissue perfusion and exchange of vital substrates. While smooth muscle cells are present within the walls of microvessels, specialized cells known as pericytes embedded in the basement membrane also play an important role in regulating tone, maintaining vascular integrity and phagocytosing cellular debris [9] (reviewed in Lee L.)

Vascular endothelial glycocalyx
The luminal surface of endothelial cells within arteries, veins and microvessels is coated with a thin (~ 500 nm) glycocalyx layer of plasma proteins, sulfated proteoglycans, glycoproteins and hyaluronan (reviewed in Weinbaum) [10]. Endothelial cell glycocalyx has several recognized functions, including maintaining vascular integrity, permeability, shear stress, mechanosensing and inflammatory responses. Leukocytes traversing a small-caliber capillary actually crush the glycocalyx. The transient deformation quickly corrects due to the elasticity of core proteins that behave like elastic fibers [11].
The properties of vascular endothelial glycocalyx layer change under inflammatory conditions. Cytokine-mediated activation of proteases partially degrade the layer permitting leukocyte rolling, tethering and recruitment [12]. An intact glycocalyx can regulate the degree of leukocyte capture, recruitment and extravasation.
Endothelial glycocalyx degradation occurs in chronic disease states like diabetes mellitus [13], significantly impacting responses to acute infectious and metabolic conditions [14, 15] (Fig. 4).
Fig. 4 Structure of the endothelial glycocalyx/endothelial surface layer. a Endothelial glycocalyx thickness is larger than the endothelial cell itself, as demonstrated by electron microscopy of ruthenium-red labeled rat myocardial capillaries. In vivo, the glycocalyx forms an even more substantial ESL, with thickness > 1 µm. b Pathological degradation of the glycocalyx/ESL during critical illnesses (such as sepsis) causes not only local endothelial injury, but also releases biologically active heparan sulfate fragments into the circulation that may influence signaling processes in an endocrine fashion. For simplicity, chondroitin sulfate and hyaluronic acid are not shown. α4 and β4 refer to glycosidic bonds connecting constituent saccharides. Inset: structure of a heparan sulfate octasaccharide fragment, demonstrating potential sites of sulfation within constituent disaccharide units
(From Oshima K. Pulmonary Circulation 2017; 8: 1–10. With permission)

Baroreceptors
The arterial baroreceptor system is intimately involved with maintaining vascular tone and blood pressure homeostasis [16]. Arterial baroreceptors (stretch receptors located in the carotid sinuses and aortic arch) provide continuous feedback on blood pressure to the central nervous system, which responds with physiological efferent autonomic activity. Activation of arterial baroreceptors in response to increased blood pressure causes activation of vagal cardio-inhibitory neurons and a decrease of sympathetic neuron discharges to the heart and peripheral resistance bed [17]. The end-result is a decrease in heart rate, cardiac contractility, peripheral vascular resistance and venous return. By contrast, a decrease in sympathetic activity and vagal inhibition, leads to tachycardia and heightened cardiac contractility, vascular resistance and venous return.
Baroreflex activity responds to the influence of many factors, including respiratory, behavioral and environmental factors. Common cardiovascular diseases, ranging from coronary artery disease, myocardial infarction, essential hypertension and heart failure are associated with baroreceptor reflex abnormalities, primarily chronic adrenergic activation [18].
Whether or not COVID-19 associated vascular injury causes baroreceptor reflex abnormalities is a question under investigation in our laboratory.