Abstract
Cyclic GMP regulates multiple cell types and functions of the cardiovascular system. This review summarizes the effects of cGMP on the growth and survival of vascular smooth muscle cells (VSMCs), which display remarkable phenotypic plasticity during the development of vascular diseases, such as atherosclerosis. Recent studies have shown that VSMCs contribute to the development of atherosclerotic plaques by clonal expansion and transdifferentiation to macrophage-like cells. VSMCs express a variety of cGMP generators and effectors, including NO-sensitive guanylyl cyclase (NO-GC) and cGMP-dependent protein kinase type I (cGKI), respectively. According to the traditional view, cGMP inhibits VSMC proliferation, but this concept has been challenged by recent findings supporting a stimulatory effect of the NO-cGMP-cGKI axis on VSMC growth. Here, we summarize the relevant studies with a focus on VSMC growth regulation by the NO-cGMP-cGKI pathway in cultured VSMCs and mouse models of atherosclerosis, restenosis, and angiogenesis. We discuss potential reasons for inconsistent results, such as the use of genetic versus pharmacological approaches and primary versus subcultured cells. We also explore how modern methods for cGMP imaging and cell tracking could help to improve our understanding of cGMP’s role in vascular plasticity. We present a revised model proposing that cGMP promotes phenotypic switching of contractile VSMCs to VSMC-derived plaque cells in atherosclerotic lesions. Regulation of vascular remodeling by cGMP is not only an interesting new therapeutic strategy, but could also result in side effects of clinically used cGMP-elevating drugs.
Highlights
Cyclic guanosine 3 -5 monophosphate is a versatile intracellular signaling molecule present in many cell types
A disease-specific role of the Cyclic guanosine -5 monophosphate (cGMP)-cGMP-dependent protein kinase type I (cGKI) axis is plausible considering our hypothesis that this pathway acts on smooth muscle-to-macrophage transdifferentiation, a process that seems to contribute to the formation of atherosclerotic lesions, but not neointima in the setting of restenosis
As discussed in this review article, in vitro and in vivo data support an important role of the NO-cGMP-cGKI axis in vascular remodeling, in the context of atherosclerosis and angiogenesis
Summary
Cyclic guanosine 3 -5 monophosphate (cGMP) is a versatile intracellular signaling molecule present in many cell types. VSMCs express various components of the cGMP signaling cascade [3,4,9] They can generate cGMP in response to NO and natriuretic peptides via NO-GCs and pGCs, respectively, and they express PDEs that degrade cGMP (e.g., PDE5) or cAMP (e.g., PDE3). The classical effects of NO and natriuretic peptides are vasodilation and regulation of blood flow It is well-accepted that these acute effects are beneficial and mediated by activation of GCs and the cGMP-cGKI pathway in VSMCs [8,9]. We will outline how the use of innovative technologies, such as cGMP imaging and cell tracking, could help to further clarify the role of cGMP in vascular plasticity in the future
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