Endogenous events modulating myogenic regulation of cerebrovascular function.
The existence of arterial myogenic tone was first described by Bayliss in 1902, however, its association with pressure-dependent membrane depolarization was not observed until 1984. The factors that mediate myogenic arterial constriction remain unknown. One possible clue was a finding by our laboratory that cerebral arterial muscle cells express CYP 4A ω-hydroxylase enzyme that catalyzes the formation of the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid (AA), the production of which increased by elevations of intravascular pressure. 20-HETE activates protein kinase C (PKC), inhibits Ca(2+)-activated K(+) (KCa) channels, depolarizes arterial muscle cell membrane, activates L-type Ca(2+) channels, increases intracellular Ca(2+) ([Ca(2+)]i) and mediates autoregulation of cerebral blood flow. Emerging evidence indicates that 20-HETE level increases in ischemia/reperfusion injury and stimulates production of reactive oxygen species (ROS) resulting in oxidative stress induced ischemic stroke injury, which can be prevented by inhibition of 20-HETE synthesis or action. The brain also expresses CYP epoxygenases that convert AA to the vasodilator epoxyeicosatrienoic acids (EETs), the production of which increases in ischemia and provide protection against ischemia-induced tissue damage. Basal or stimulus released ROS act to modify cerebral myogenic tone. Similar to other enzymes CYP epoxygenase and ω-hydroxylase also generate ROS that modify myogenic cerebral reactivity. Hypoxia per se or adenosine released during hypoxia induces increased production of ROS that alter cerebrovascular function. The capacity of the brain to express CYP enzymes that produce bioactive EETs and 20-HETE and generate ROS has a significant bearing in regulating the dynamics of cerebral blood flow and serve as potential therapeutic targets for the management of pathologic disorders of the cerebral circulation.
Cardiovascular Research Center, Medical College of Wisconsin, USA.
Debebe
D
Gebremedhin
Cardiovascular Research Center, Medical College of Wisconsin, USA.
Sandeep
S
Gopalakrishnan
Medical College of Wisconsin, Department of Physiology and cardiovascular Research Center, Watertown Plank Road, Milwaukee, WI, 53226. dharder@mcw.edu.
David R
DR
Harder
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D003577:Cytochrome P-450 Enzyme System