What is Endothelial Function?
Once thought to be a “passive” barrier, the endothelium is now recognized as a dynamic and active transducer of cellular signals within the vascular system, thanks to landmark experiments by Furchgott and colleagues demonstrating the obligatory role of an intact endothelium to elicit acetylcholine-induced vasodilation of vascular smooth muscle(1) and subsequent discovery of a diffusible substance released by the endothelium now recognized as nitric oxide (NO).
A healthy, functional endothelium senses and responds to mechanical and chemical signals by synthesizing and releasing vasoactive molecules, primarily (but not exclusively) NO, which diffuse into adjacent vascular smooth muscle to elicit their effects including vascular smooth muscle relaxation and vessel dilation. Molecules in the circulation with vasoactive properties include NO, bradykinin, adenosine, vascular endothelial-growth factor, thrombin, serotonin, and prostacyclin, among others.(2) Of these, NO, prostacyclin, and endothelium-derived hyperpolarizing factors are endothelial in origin.(3)
In addition to chemical signals, the shear forces of blood flow transduce mechanical signals to the endothelium, leading to the production of NO from activated endothelial nitric oxide synthase (eNOS) and the co-factors BH4 and L-arginine. Once produced, NO diffuses to underlying vascular smooth muscle where it stimulates guanylyl cyclase, catalyzing the conversion of guanosine triphosphate to cyclic guanosine monophosphate. Cyclic guanosine monophosphate activates downstream kinases including protein kinase G, leading to an inactivation of calcium release channels and causing vascular smooth muscle relaxation. Vascular relaxation can also occur in response to NO-independent signals including endothelium-derived hyperpolarizing factors and prostacyclin, the latter which is also stimulated by shear stress and acetylcholine.(3)
Opposing the actions of vasodilators within the endothelium are molecules known as endothelium-derived vasoconstrictors, and include endothelin-1 and angiotensin II, along with vasoconstrictor prostanoids. Endothelin-1, while primarily a vasoconstrictor, also inhibits the actions of NO and at high concentrations can promote inflammation and smooth muscle proliferation.(4) Like NO, endothelin-1 is produced by the vascular endothelium, but other sources include vascular smooth muscle, leukocytes, and macrophages(3) Endothelin-1 mediates its vascular effects through ETA and ETB receptors, though it is generally accepted that the ETA receptors mediate the vasoconstrictive actions of endothelin-1.(4) Angiotensin-II is synthesized by endothelial cells and exerts its vasoactive effects by binding to angiotensin I and II receptors within the vasculature where it causes vasoconstriction and expression of adhesion molecules, cytokines, and growth factors. As such, angiotensin II is implicated in the initiation and progression of atherosclerosis and endothelial dysfunction.
In healthy endothelium, vascular homeostasis is regulated by a balance of vasorelaxing/anti-atherogenic and vasoconstricting/pro-atherogenic factors. NO plays a considerable role in maintaining vascular wall health by exerting anti-inflammatory, anti-proliferative, anti-coagulative, and anti-atherogenic actions. Thus, endothelial homeostasis is governed, in part, by the balance between vasodilatory actions of NO and vasoconstrictor actions of endothelin-1.(5)
Endothelial dysfunction, on the other hand, is characterized by a state of vasodilator/vasoconstrictor imbalance and cell proliferation which reduces the vasodilatory capacity of vessels and induces a pro-thrombotic and pro-atherosclerotic phenotype. Some have proposed that endothelial dysfunction may be more appropriately termed “endothelial activation”,(6) while a more classical definition includes a failure of the endothelium to elicit NO-mediated vasodilation due to either decreased production or increased degradation of NO.(2) Endothelial dysfunction can also be characterized by an imbalance of NO and endothelin-1 within the vasculature. In a dysfunctional endothelium, reactive oxygen species (ROS), inflammation, increased vasoconstrictors, and increased presence of cytokines, chemokines, and adhesion molecules leads to an activated endothelial phenotype characterized by a loss of NO-mediated vasodilation. In addition to a loss of vasodilation, reduced NO bioavailability in a dysfunctional endothelium results in the loss of NO’s protective effects on platelet aggregation, coagulation, and cell proliferation,(2) leading to endothelial dysfunction and promoting atherogenesis.
A large contributor to endothelial dysfunction is the production of ROS within the vasculature. Reactive oxygen species cause eNOS uncoupling, in which eNOS, rather than generating NO, becomes a free radical-generating enzyme and produces hydrogen peroxide and/or superoxide. In addition to causing eNOS uncoupling, superoxide can interact directly with and inactivate NO to form peroxynitrite, a damaging oxidant with no vasoactive properties. Evidence for a role of free radical-mediated NO degradation in vascular dysfunction is evidenced by the fact that endothelial superoxide production is associated with reduced NO-mediated vasorelaxation,(7) and that animal models of increased superoxide production demonstrate worse acetylcholine-mediated vasodilation,(8) while superoxide scavengers restore endothelium-dependent vasodilation.(9)
An incredibly small part of our body (size-wise, at least), but a system that has vast importance and wide physiological implications for performance, health, and longevity.
References
1. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288(5789):373–6.
2. Behrendt D, Ganz P. Endothelial function: From vascular biology to clinical applications. The American Journal of Cardiology. 2002;90(10):L40–8.
3. Cahill PA, Redmond EM. Vascular endothelium — Gatekeeper of vessel health. Atherosclerosis. 2016;248:97–109.
4. Thorin E, Webb DJ. Endothelium-derived endothelin-1. Pflugers Archiv : European journal of physiology. 2010;459(6):951–8.
5. Townsend Raymond R, Wilkinson Ian B, Schiffrin Ernesto L, et al. Recommendations for Improving and Standardizing Vascular Research on Arterial Stiffness. Hypertension. 2015;66(3):698–722.
6. Deanfield John E, Halcox Julian P, Rabelink Ton J. Endothelial Function and Dysfunction. Circulation. 2007;115(10):1285–95.
7. Guzik TJ, West NEJ, Black E, et al. Vascular Superoxide Production by NAD(P)H Oxidase : Association With Endothelial Dysfunction and Clinical Risk Factors. Circulation research. 2000;86(9):e85–90.
8. Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. The Journal of clinical investigation. 1993;91(6):2546–51.
9. Taddei Stefano, Virdis Agostino, Ghiadoni Lorenzo, Magagna Armando, Salvetti Antonio. Vitamin C Improves Endothelium-Dependent Vasodilation by Restoring Nitric Oxide Activity in Essential Hypertension. Circulation. 1998;97(22):2222–9.
