Abstract
Nitric oxide (NO) is an important vasoprotective molecule that serves not only as a vasodilator but also exerts antihypertrophic and antiproliferative effects in vascular smooth muscle cells (VSMC). The precise mechanism by which the antihypertrophic and antiproliferative responses of NO are mediated remains obscure. However, recent studies have suggested that one of the mechanisms by which this may be achieved includes the attenuation of signal transduction pathways responsible for inducing the hypertrophic and proliferative program in VSMC. Endothelin-1 is a powerful vasoconstrictor peptide with mitogenic and growth stimulatory properties and exerts its effects by activating multiple signaling pathways which include ERK 1/2, PKB and Rho-ROCK. Both cGMP-dependent and independent events have been reported to mediate the effect of NO on these pathways leading to its vasoprotective response. This review briefly summarizes some key studies on the modulatory effect of NO on these signaling pathways and discusses the possible role of cGMP system in this process.
Highlights
Increased vascular smooth muscle cell (VSMC) hypertrophy, migration and proliferation are among key events that contribute to remodeling of the vasculature associated with cardiovascular diseases
The aim of this review is to highlight the effect of the nitric oxide (NO) system on the key signaling pathways induced by ET-1 that are linked to hypertrophy and proliferation of VSMC
As was the case with ERK pathway, treatment with L-NAME potentiated ET-1-induced phosphorylation of protein kinase B (PKB) (Fig. 2B), further suggesting a modulatory role of the NO system on ET-1-induced signaling responses. In these studies, 8-Br-cyclic guanosine 3’5’-monophosphate (cGMP) mimicked and ODQ restored the inhibitory effect of SNAP on ET-1-induced phosphorylation of PKB (Figs. 4C and 4D) [76]. These studies suggested a role of cGMP-dependent events in modulating NO-induced inhibition of ERK and PKB signaling pathways induced by ET-1
Summary
Increased vascular smooth muscle cell (VSMC) hypertrophy, migration and proliferation are among key events that contribute to remodeling of the vasculature associated with cardiovascular diseases. Nitric oxide (NO), originally described as a non-prostaglandin, endothelium-derived relaxing factor (EDRF), in addition to its potent vasodilator action, has emerged as an important vasculo-protective agent through its ability to exert antihypertrophic, anti-proliferative and anti-apoptotic responses in the cardiovascular system [3,4,5,6,7]. The balance between these two endothelium-derived opposing agents helps regulate vascular homeostasis. The aim of this review is to highlight the effect of the NO system on the key signaling pathways induced by ET-1 that are linked to hypertrophy and proliferation of VSMC
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