Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 655

Table 10.16. Individual and combined effects of gasotransmitters in vascular smooth myocytes
(Source: [ 1325 ]; : inhibition; cGMP: cyclic guanosine monophosphate;

BK Ca ,IK Ca ,SK Ca :large-[K Ca 1.1], intermediate- [K Ca 3.1], and small-conductance [K Ca 2]
calcium-sensitive K + channel; K AT P : ATP-dependent K + channel [K IR 6.2]; sGC: soluble guany-
late cyclase). Gasotransmitters (NO, CO, and H 2 S) may antagonize or potentiate their production,
molecular targets, and mutual interaction. Nitric oxide can play a more important vasorelaxant role
in large arteries such as aorta; hydrogen sulfide in peripheral resistive arteries such as mesenteric
and coronary arteries, acting as an endothelium-derived hyperpolarizing factor. Both NO and CO
have a synergistic effect on BK Ca channels in vSMCs, as they increase its opening probability.

⊕−→ : stimulation; −→

Gasotransmitter Effect

CO sGC-cGMP-PKG

PKG Ca 2 + influx from

endoplasmic reticulum
PKG

−→

−→ Ca V 1.2

PKG ⊕−→ BK Ca

⊕−→ BK Ca

(BK Ca subunit)

Hyperpolarization

α

H 2 S −→ PDE5

⊕−→ IK Ca ,SK Ca

⊕−→ K AT P

Hyperpolarization

NO sGC-cGMP-PKG

⊕−→ BK Ca
(BK Ca β subunit)
Hyperpolarization

as well as vasodilatation [ 1328 ]. 76 Nitric oxide binds to soluble guanylate cyclase
that generates cGMP second messenger. The latter activates protein kinase-G;
it is degraded by PDE5a phosphodiesterase. Protein kinase-G1 is needed for
endothelial cell proliferation and migration. Hydrogen sulfide precludes PDE5a
activity. Exposure of endothelial cells to H 2 S increases intracellular cGMP level
in a NO-dependent manner. Hence, these 2 gasotransmitters cooperate to ele-
vate and maintain intracellular cGMP concentration. Hydrogen sulfide supports
the phosphorylation of the PKG substrate vasodilator-stimulated phosphoprotein
(VASP). In addition, H 2 S increases NOS3 phosphorylation at Ser1177 (activation)
and decreases that at Thr495 (inhibition). Moreover, H 2 S activates the PI3K-PKB
axis.

76 Inhibition of endothelial NO synthase (NOS3) or PKG1 abolishes H 2 S-triggered angio-
genesis and attenuates H 2 S-primed vasorelaxation. Conversely, inactivation of H 2 S synthase
cystathionine

γ

-lyase supresses NO-stimulated cGMP accumulation and angiogenesis and reduces
acetylcholine-stimulated vasorelaxation [ 1328 ].