Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 586

9.10.7.3 Reactive Oxygen Species

Reactive oxygen species (ROS) are second messengers that contribute to normal
cell functioning. However, excessive ROS production or dysregulated metabolism
(oxidative stress) elevates vascular smooth myocyte contractility and growth and
causes inflammation as well as systemic and pulmonary hypertension.
Reactive oxygen species that oxidize their substrates are involved in endothelial
cell signaling, especially that assigned to vascular remodeling and endothelium-
regulated vasorelaxation.
Stress-activated NADPH oxidase produces reactive oxygen species in the vessel
wall. 180 Reactive oxygen species interact with NO to produce peroxynitrite that
activates matrix metallopeptidases, leading to vessel wall remodeling [ 1140 ].
Hydrogen peroxide activates AMP-activated protein kinase in cultured bovine
aortic endothelial cells [ 1141 ]. Activated by elevated AMP/ATP ratio, AMPK
switches ATP-generating catabolism on and anabolism off. Endothelial AMPK
is activated by numerous stimuli, such as hypoxia, peroxynitrite (ONOO − ), ad-
iponectin, vascular endothelial growth factor, and vasoactive mediators, such as
sphingosine 1-phosphate, bradykinin, and thrombin. Enzyme AMPK phosphory-
lates (activates) NOS3 (Ser1177) [ 1141 ]. Hydrogen peroxide (H 2 O 2 ) activates in
a time- and dose-dependent manner Ca 2 + -calmodulin-dependent protein kinase
kinase-

that leads to AMPK phosphorylation. In addition, liver kinase-B LKB1, is
phosphorylated on H 2 O 2 administration, but LKB1 plays a minor role. On the other
hand, Ca 2 + -calmodulin-dependent endothelial nitric oxide synthase NOS3 prevents
AMPK activation (negative feedback) [ 1141 ].
Hydrogen peroxide synthesized by nitric oxide synthase NOS1 is responsible
for acetylcholine-induced endothelium-dependent relaxation of smooth myocytes
of wall media [ 1142 ]. Isoform NOS1 is constitutively expressed in the endothelium
of mouse aorta. Hydrogen peroxide produced by NOS1 can act as a coparticipant in
endothelium-dependent vasodilation.
Reactive oxygen species cause vasoconstriction and -dilation according to
vasculature compartment, vessel size, nature of preconstriction, and ROS type and
amount. Superoxide anion and its product hydrogen peroxide actually have distinct
actions on the vasculature. Superoxide precludes endothelium-dependent relaxation
by NO scavenging in both pulmonary and systemic arteries. Hydrogen peroxide fa-
vors metabolic dilation in the coronary circulation via K + channels and subsequent
hyperpolarization (predominantly via K V and possibly also BK channels) [ 1143 ].
Both superoxide and hydrogen peroxide provoke vasoconstriction in rat pulmonary
arteries, mainly acting via RoCK kinase that phosphorylates PP1 r12a , which inhibits
myosin phosphatase, thus enhancing MLC20 phosphorylation.

β

180 Subunit NOx organizer NOxO2 of NADPH oxidase upregulates production of reactive oxygen
species and matrix metallopeptidases.