Endothelial Function

The endothelium is the single layer of cells lining every blood vessel, and it is far more than a passive barrier. It senses the shear of flowing blood and circulating signals, releases vasoactive mediators that relax or constrict the underlying smooth muscle, controls the permeability of the vessel wall, and regulates coagulation, inflammation, and new-vessel growth. Endothelial function is now treated as a core determinant of vascular health.

Definition

The vascular endothelium is the continuous monolayer of cells lining the lumen of blood vessels; endothelial function refers to its active regulation of vascular tone, permeability, haemostasis, inflammation, and angiogenesis.

Scope

This topic covers the physiological roles of the vascular endothelium: endothelium-dependent control of vascular tone (notably via nitric oxide), barrier and permeability function through inter-endothelial junctions, mechanotransduction of shear stress, and the broader homeostatic roles of the endothelium. It does not cover clinical management of endothelial dysfunction.

Core questions

• How does the endothelium control the tone of the underlying smooth muscle?
• What is the role of nitric oxide in endothelium-dependent vasodilation?
• How does the endothelium regulate the permeability of the vessel wall?
• How do endothelial cells sense and respond to the shear stress of flow?

Key concepts

• Endothelium-dependent vasodilation
• Nitric oxide and endothelial nitric oxide synthase
• Shear-stress mechanotransduction
• Inter-endothelial junctions and barrier function
• Vascular permeability
• Endothelial regulation of haemostasis and inflammation
• Endothelial cell metabolism and angiogenesis

Key theories

Endothelium-derived relaxing factor / nitric oxide

Intact endothelium is required for agonists such as acetylcholine to relax arterial smooth muscle; the responsible diffusible signal, endothelium-derived relaxing factor, was identified as nitric oxide produced by endothelial nitric oxide synthase, establishing the endothelium as an active regulator of vascular tone.

Mechanisms

Endothelial cells transduce mechanical shear and chemical agonists into the release of vasoactive mediators. The pivotal observation that endothelium is obligatory for acetylcholine-induced arterial relaxation (Furchgott & Zawadzki, 1980) led to identifying the relaxing factor as nitric oxide, generated by endothelial nitric oxide synthase and diffusing to the smooth muscle to raise cyclic GMP and cause relaxation (Forstermann & Sessa, 2011). The endothelium also forms the vessel's permeability barrier through tightly regulated inter-endothelial junctions that open and close to control the passage of fluid and solutes (Bazzoni & Dejana, 2004). Beyond tone and barrier function, endothelial cells direct angiogenesis and adapt their metabolism to vascular demands (Eelen et al., 2015), and they regulate coagulation and leukocyte adhesion at the blood-wall interface.

Clinical relevance

Impaired endothelium-dependent vasodilation (endothelial dysfunction) is an early correlate of many vascular conditions and is widely studied as a vascular phenotype. This entry explains the underlying physiology as reference material; it is not clinical guidance and does not direct diagnosis or treatment.

Evidence & guidelines

The physiological foundation is the experimental demonstration of endothelium-dependent relaxation (Furchgott & Zawadzki, 1980) and the molecular characterisation of nitric oxide synthases (Forstermann & Sessa, 2011), complemented by reviews of endothelial junctions and barrier function (Bazzoni & Dejana, 2004) and of endothelial metabolism (Eelen et al., 2015).

History

Before 1980 the endothelium was largely regarded as an inert lining. Furchgott and Zawadzki's demonstration that endothelial cells are required for acetylcholine to relax arteries (Furchgott & Zawadzki, 1980) revealed an endothelium-derived relaxing factor, subsequently identified as nitric oxide; this work, recognised by a Nobel Prize, launched the field of endothelial biology and the later detailing of nitric oxide synthases (Forstermann & Sessa, 2011), endothelial junctions (Bazzoni & Dejana, 2004), and endothelial metabolism (Eelen et al., 2015).

Key figures

• Robert F. Furchgott
• Salvador Moncada
• William C. Sessa
• Elisabetta Dejana
• Peter Carmeliet

Seminal works

• furchgott-zawadzki-1980
• forstermann-sessa-2011
• bazzoni-dejana-2004

Frequently asked questions

What does the endothelium actually do besides lining vessels?

It actively regulates vascular tone, controls how permeable the vessel wall is, senses blood flow, and helps govern clotting, inflammation, and the growth of new vessels.

What is endothelium-dependent vasodilation?

It is relaxation of vascular smooth muscle that requires an intact endothelium, classically because the endothelium releases nitric oxide that diffuses to the smooth muscle and relaxes it.