What is endothelial function?

This is an excerpt from Advanced Cardiovascular Exercise Physiology-2nd Edition by Denise L. Smith & Bo Fernhall.

Properly functioning endothelium is critical to the health and function of the cardiovascular system. This section briefly describes the major functions of the endothelium. Specific functions are addressed in more depth ­later in this chapter and in subsequent chapters. As shown in figure 7.4, the vascular endothelium has multiple functions, and ­these functions are often specific to the site in the vascular tree. The primary functions of the endothelium include

1. serving as a selectively permeable barrier to regulate blood–­tissue exchange,
2. regulating vascular tone,
3. releasing anticlotting and proclotting ­factors to control hemostasis,
4. participating in inflammatory defense against pathogens, and
5. initiating new blood vessel formation (angiogenesis).

The exchange of fluids, nutrients, and gases between the blood and tissues occurs primarily within the capillaries (figure 7.4, #1). The primary role of the endothelium in regulating this exchange is to form a semipermeable membrane that retains blood within the vessel and allows nutrients and gases to move into the tissue. ­These functions rely on structural features of the endothelium are due largely to the glycocalyx and the intracellular junctions. While lipid-­soluble substances diffuse through the endothelial cells, small, water-­soluble substances diffuse through the intracellular junctions. Large molecules, such as immunoglobulins and protein-­bound hormones, pass from the circulation to the under­lying tissue via the caveola–­vesicle system. ­These flask-­shaped structures are actually invaginations into the cell membrane that permit the endothelial cells to take up substances from the blood by the pro­cess of endocytosis. The movement of fluid and nutrients across the endothelium occurs primarily at the capillary level, due to the thinness of the vessel wall.

Vascular tone is determined by the degree of smooth muscle contraction in the tunica media (figure 7.4, #2). When smooth muscle contracts (vasoconstriction), it decreases the dia­meter of the blood vessels and decreases blood flow. Conversely, relaxation of the smooth muscle (vasodilation) increases the dia­meter of a blood vessel and results in increased blood flow. Endothelium that lines the arteries and arterioles plays a central role in regulating contraction of the smooth muscle cells in the tunica media and thereby helps control blood flow. Endothelial cells respond to changing conditions, especially shear stress, and release chemical mediators that lead to vasodilation (nitric oxide, NO; prostacyclin, PGI₂) and vasoconstriction (endothelin) of the smooth muscle. The balance of ­these mediators plays an impor­tant role in determining blood flow distribution to vari­ous organs. The importance of this role of endothelium is reinforced by the fact that endothelial dysfunction is often assessed by the ability of smooth muscle to vasodilate in response to a stimulus.

­Factors released from the endothelium have a potent effect on blood clotting potential (figure 7.4, #3). In fact, some of the same vasodilatory ­factors, notably NO and PGI₂, that cause relaxation of under­lying smooth muscle are also released into the bloodstream where they have an inhibitory effect on platelet aggregation, making a clot formation less likely. Thus, the release of ­these ­factors has the simultaneous and mutually reinforcing effect of increasing blood flow and maintaining blood fluidity. In fact, the endothelium is one of the only surfaces, ­either natu­ral or synthetic, that can maintain blood in its fluid state during prolonged contact. This ability is due to the presence of heparin sulfate proteoglycan molecules on the surface of endothelial cells (Libby, 2005). ­Under certain circumstances, namely vascular injury, endothelium also secretes von Willebrand ­factor (vWF), which is produced in specialized organelles called Weibel-­Palade bodies. Von Willebrand ­factor promotes platelet adhesion and plays a role in the coagulatory cascade. Thus, the endothelium plays a critical role in maintaining blood fluidity and fostering clot formation. The role of the endothelium in maintaining homeostatic balance is discussed fully in chapter 8.

The endothelium is also essential in the inflammatory and immune defense against pathogens (figure 7.4, #4). In response to injury or invasion, venular endothelium produces adhesion molecules that cause circulating leukocytes to be attached to the endothelium. Several adhesion molecules are involved in causing a leukocyte to adhere to the endothelium. P-­selectin, which is released from Weibel-­Palade bodies, and E-­selectin cause a loose bond between the leukocyte and the endothelium. Intracellular adhesion molecules (ICAMs) and vascular adhesion molecules (VCAMs) then cause a tighter bonding of the leukocyte and endothelium. Fi­nally, the leukocyte begins to move into the intracellular junction; it then moves into the tissue through the pro­cess of diapedesis. The final step is dependent on platelet–­endothelial cell adhesion molecules (PECAM). Venular endothelium can also produce large endothelial gaps that allow for increased delivery of immunoglobulins (antibodies) to the tissue to provide an immune response in response to infection. Plasma also passes through ­these endothelial gaps, leading to the swelling that characterizes inflammation.

The endothelium plays a critical role in the development of new vessel formation, termed angiogenesis (figure 7.4, #5). Capillary sprouting initiates all new blood vessels. Endothelial cells can be stimulated to divide rapidly when ­there is a need for new vessel formation (for growth or repair or to support new tissue). New vessel formation begins with the breakdown of the basal lamina and the sprouting of the endothelium from the side of a capillary or venule. The cell extensions put out by the endothelium, called pseudopodia, grow ­toward the stimulus for new blood supply. ­These pseudopodia are enlarged by cytoplasmic growth ­until they divide into ­daughter cells. Vacuoles then digest material within the new ­daughter cells. Eventually the vacuoles of the ­daughter cells fuse, resulting in a new lumen. The entire pro­cess continues ­until the new sprout encounters another capillary to connect to.

Case Study

COVID-19 and the Vascular Endothelium
Sonya is a 36-­year-­old female who enjoys hiking with her ­family but does not engage in regular programmed fitness training. She has a BMI of 32 and a resting BP of 126/88 mmHg. Despite trying to practice social distancing as recommended, Sonya developed respiratory symptoms and ­later tested positive for COVID-19. Sonya’s doctor advised her that her recovery would include allowing time for the lungs and vascular endothelium to heal. Sonya knew that the lungs ­were affected by COVID-19 but was surprised to hear about the vascular endothelium.

Questions

1. How does the SARS-­CoV-2 virus affect the endothelium?
2. What are the consequences of endothelial disruption with COVID-19?