Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 592

especially upon small changes in pH (slight acidosis [pH 7.0-7.1] [ 1150 ]) and O 2
and CO 2 concentration (brief periods of hypoxia and hypercapnia [ 1151 ]), hence
enabling matching of O 2 supply by the microvasculature to demand, as well as in
osmotic pressure 189 and hemodynamic stress.
Red blood capsules experience variations in hemodynamic stress along the
vascular network. Increased shear inside narrow capillaries and small arterioles
causes RBC deformation. The latter triggers ATP release. The amount of ATP
released depends on the shear magnitude and duration [ 1153 ]. The activity of cystic
fibrosis transmembrane conductance regulator, or ATP-binding cassette transporter
ABCc7, is required for deformation-induced ATP release from RBCs [ 1154 ].
The transfer ATPase CFTR does not convey ATP, but regulates other carriers, among
which those that enable ATP egress. The AC-cAMP pathway is involved in ATP
release [ 1156 ].
The paracrine regulator ATP causes vasodilation by releasing nitric oxide from
endothelial cells via P2Y receptors. In addition to reduction of pulmonary vascular
resistances, 190 liberation from red blood capsules of ATP causes vasodilation of
cerebral arterioles during hypoxia.
The gaseous mediator carbon monoxide (CO) is a vasodilator in some com-
partments such as liver sinusoids, but in the cerebral circulation, CO elicits
vasoconstriction. On the other hand, hydrogen sulfide, another gasotransmitter, is a
vasodilator in both the peripheral and cerebral circulations. It causes S-sulfhydration
(activation) of ATP-sensitive potassium channels, thereby hyperpolarizing the
vascular endothelial and smooth muscle cells. Heme oxygenase HO2, an O 2
sensor, uses O 2 to generate carbon monoxide. The latter, but not NO, inhibits
astrocytic cystathionine

-synthase, which thus acts as a CO sensor, in addition
to be a generator of hydrogen sulfide. During hypoxia, HO2 activity is prevented,
CBS inhibition is relieved, thereby produced H 2 S elicits vasodilation of cerebral
arterioles [ 1157 ].
In fact, hypoxia via non-vascular cerebral components stimulates the production
of various vasodilators, such as potassium and hydrogen ions, prostaglandins, and
adenosine [ 1158 ]. Reactive hyperemia , i.e., the local increase in blood flow follow-
ing an intensification of tissue metabolism, is related to metabolic vasodilation trig-
gered by active cells that surround arterioles and release vasodilators. Vasodilatory
tissue metabolites and ions include, in addition to hypoxia: (1) adenosine generated
from AMP; (2) carbon dioxide formed during increased oxidative metabolism;
(3) lactic acid produced by anaerobic metabolism; (4) H + ion associated with CO 2
augmentation, (5) liberated K + ion that hyperpolarizes and relaxes vascular smooth
myocytes. In addition, hypoxia also promotes the release of excitatory amino acids
by neurons. These amino acids augment the export of vasodilators. Direct vascular

β

189 Extracellular ATP supports regulatory RBC volume decrease via Ca 2 + and ATP-dependent K +
efflux, thereby reducing hemolysis [ 1152 ].
190 In primary pulmonary hypertension, RBCs have a reduced deformability and ATP is not
released [ 1155 ].