Endothelium and Vascular Tone

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In addition to its fundamental role in controlling vascular permeability, endothelium is also a major regulator of vascular tone. The primary mechanism by which endothelium regulates tone of underlying vascular muscle under normal conditions is by release of endothelium-derived relaxing factor(s) (EDRFs). These factors include nitric oxide (NO), endothelium-derived hyperpolarizing factor(s)(EDHFs), and prostacyclin (Figure 1).

Under normal conditions, most studies indicate that nitric oxide is the predominant EDRF in the cerebral circulation. In both pial (vessels on the surface of the brain) and parenchymal arterioles, many lines of evidence illustrate that nitric oxide from endothelium influences basal tone and mediates the majority of the response to acetylcholine (the classic endothelium-dependent agonist), other receptor-mediated agonists, and increased shear stress (Figure 1). Once it diffuses to vascular muscle, nitric oxide produces relaxation predominantly via activation of soluble guanylate cyclase and increased production of cGMP (Figure 1). This mechanism of endothelium-dependent relaxation may differ from that seen in select peripheral microvascular beds where some studies have suggested that EDHF is the major EDRF in microvessels.

The cerebral microcirculation is unusual in that responses to bradykinin, another endothelium-dependent

Shear Stress

Acetylcholine Bradykinin ADP, ATP, UTP

Shear Stress

Acetylcholine Bradykinin ADP, ATP, UTP

Figure 1 Schematic representation of major mechanisms of endothelium-dependent relaxation of vascular muscle in cerebral microves-sels. Nitric oxide (NO) is produced by the endothelial isoform of NO-synthase (eNOS) in response to activation of the M5 subtype of muscarinic receptor and other endothelium-dependent stimuli. NO diffuses to vascular muscle, where it activates soluble guanylate cyclase (sGC), causing increased production of cyclic GMP (cGMP), activation of cGMP-dependent protein kinase I, and relaxation. In contrast, bradykinin (via activation of the B2 subtype of receptor) activates cyclooxygenase-1 (COX-1), resulting in production of reactive oxygen species (ROS) including hydrogen peroxide (H2O2). H2O2 activates potassium channels (K+ channels) in vascular muscle, producing membrane hyperpolarization and relaxation. In response to some purines (ATP, UTP, ADP), endothelium can produce EDHF through an unknown pathway. By definition, EDHF produces relaxation of vascular muscle by activation of potassium channels and membrane hyperpolarization. In some vessels, cGMP can also activate potassium channels.

agonist, are mediated by reactive oxygen species (ROS) in normal cerebral arterioles. It is not entirely clear which reactive oxygen species specifically mediates this response, but hydrogen peroxide may be responsible for bradykinin-mediated vasodilatation (Figure 1).

In addition to modulation of microvascular function, nitric oxide and reactive oxygen species may affect microvascular structure. For example, preliminary findings indicate that genetic deficiency in superoxide dismutase-1 (SOD-1), the CuZn isoform of SOD, produces increases in superoxide and hypertrophy of cerebral arterioles. Increases in cross-sectional area of the vessel wall (hypertrophy) may have functional consequences because hypertrophy of vascular muscle can impair maximal vasodilator capacity.

Although nitric oxide is the primary mediator of microvascular responses to many endothelium-dependent stimuli, EDHF may mediate a major portion of the response of cerebral microvessels to other endothelium-dependent stimuli including selected purines (Figure 1). To date, there has been no convincing evidence that EDHF or reactive oxygen species influence resting tone of cerebral arterioles under normal conditions.

In summary, endothelium-derived nitric oxide influences resting microvascular tone and is a major EDRF in brain. For selected stimuli, however, reactive oxygen species and EDHF can also be important EDRFs in the cerebral circulation.

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