**1. Introduction**

Progressive Peripheral Atherosclerosis in the General Population. *Circulation*, Vol.

[54] Tsimikas, S.; Tsironis, LD. & Tselepsis, AD. (2007). New Insights Into the Role of Lip‐ oprotein (a)-Associated Lipoprotein-Associated Phospholipase A2 in Atherosclerosis and Cardiovascular Disease. *Arteriosclerosis Thrombosis and Vascular Biology*, Vol.27,

[55] Zalewski, A. & Macphee, C. (2005). Role of Lipoprotein-Associated Phospholipase A2 in Atherosclerosis Biology, Epidemiology, and Possible Therapeutic Target. *Arte‐ riosclerosis, Thrombosis and Vascular Biology*, Vol.25, No.5, (May 2005), pp. 923- 931,

[56] Winkler, K.; Winkelmann, BR.; Scharnagl, H.; Hoffmann, MM.; Grawitz, AB.; Nauck, M. et al. (2005). Platelet-Activating Factor Acetylhydrolase Activity Indicates Angio‐ graphic Coronary Artery Disease Independently of Systemic Inflammation and Oth‐ er Risk Factors: The Ludwigshafen Risk and Cardiovascular Health Study.

112, pp. 976- 983,ISSN:0009-7322

ISSN 1049-8834

120 Current Trends in Atherogenesis

No.10, (October 2007), pp. 2094-2099, ISSN 1079-5642

*Circulation*, Vol. 111, No.8, pp. 980-987,ISSN :0009-7322

Vascular Smooth Muscle Cells (VSMC) are highly specialized cells whose principal functions are contraction and regulation of blood vessel tone-diameter, blood pressure, and blood flow distribution. In healthy adult blood vessels, these cells proliferate at a very low rate, exhibit very low synthetic and migratory activity and express a unique repertoire of contractile proteins, ion channels, and signalling molecules required for the cell's contractile function. VSMC undergo significant phenotypic modulation following vascular injuries including hypoxia, oxidative stress and mechanical injury. This phenotypic transition is mainly charac‐ terized by the loss of contractility and the acquisition of a proliferative, migratory and synthetic phenotype. These drastic phenotypic alterations allow VSMCs to migrate from the media to the intima of the arterial wall where they proliferate and secrete an extracellular matrix and pro-inflammatory molecules. This phenotypic transition, also called the trans-differentiation process, plays a critical role in pathological vascular remodellings such as atherosclerosis, postangioplasty restenosis, bypass vein graft failure, and cardiac allograft vasculopathy [1,2]. Hypoxia, mechanical stress and oxidative stress can induce VSMC trans-differentiation directly or indirectly by stimulating the release of pro-inflammatory molecules and growth factors from endothelium, macrophages, T lymphocytes or VSMC themselves. Signalling pathways involved in VSMC trans-differentiation are diverse. Among them, the 3'-5'-cyclic adenosine monophosphate (cAMP) signalling pathway stands out since cAMP is not only described to play important roles both in differentiated and transdifferentiated VSMCs, but can also have opposite effects in VSMCs with the same phenotype. Indeed, in trans-differen‐ tiated VSMCs, cAMP has dual opposite effects on migration and inflammation and stops cell proliferation. Alternatively, in differentiated VSMCs, cAMP induces relaxation, expression of

© 2013 Glorian and Limon; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

contractile proteins, maintenance of a low proliferation rate and can stimulate or inhibit apoptosis (Figure 1). The diversity of cAMP effects in VSMC (and in cells in general), is due to the ability of this second messenger to transduce extracellular signals in a compartmentalized manner, allowing individual stimuli to produce distinct pools of cAMP localized in discrete subcellular regions. These pools of cAMP are produced near a subset of cAMP effectors, themselves located near their substrates and engage specific cell responses according to the cellular context [3]. Adenylyl cyclases (AC), phosphodiesterases (PDE) and the scaffolding proteins A kinase anchored proteins (AKAPs) play a determinant role in cAMP compartmen‐ talization. Final cAMP effect depends on which isoforms of these proteins are expressed. During the VSMC trans-differentiation process, important changes in the expressions of such proteins occur, allowing a re-organization of the cAMP signalling compartmentalization, therefore giving VSMC the ability to acquire properties specific to the trans-differentiated state. After a presentation of the cAMP signalling pathway, this chapter discusses data demonstrat‐ ing the diversity of roles of cAMP in differentiated and transdifferentiated VSMCs.

then activate or inhibit distinct intracellular signalling cascades. The αs of the Gs subtype activates adenylyl cyclases (AC) witch catalyzes the synthesis of cAMP from ATP. Increased levels of cAMP are translated into cellular responses by cAMP effectors. The best known is the c-AMP dependant protein kinase A (PKA), but also include cyclic-nucleotide gated ion channels (CNGCs) and the recently discovered Rap1-guanine nucleotide exchange factor (Epac), three effectors known to mediate a multitude of cAMP signalling pathways. (Figure 2). The end of cAMP signalling is achieved by its decomposition into AMP catalyzed by phosphodiesterases (PDEs) and its active efflux through transporters of the multidrug resistance-assocuated protein (MRP) family [4,5]. One particularity of the cAMP signalling pathway is its high degree of compartmentalization. Multiprotein complexes organize the location of the different cAMP effectors to specific subcellular locations and allow cAMP to propagate a plethora of cell responses in a spatio-temporal manner [3]. These multiprotein complexes are at the foundation of cAMP compartmentalization, they involve AC, the

The Role of Cyclic 3'-5' Adenosine Monophosphate (cAMP) in Differentiated and Trans-Differentiated...

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**Figure 2.** Cyclic adenosine 3', 5'-monophosphate (cAMP) is produced from ATP by adenylyl cyclase (AC) upon activa‐ tion of Gs-protein coupled receptors. The local concentration and distribution of cAMP gradients is limited by phos‐ phodiesterases (PDE) which generate localized pools of cAMP throughout the cell. The increase in cAMP is translated to cellular responses by the cAMP effectors protein kinase A (PKA), EPAC (exchange protein activated by cAMP) and cyclic nucleotide -gated ion channels (CNGCs). A kinase anchored proteins (AKAPs) target cAMP effectors to distinct cell compartments. They also intract with AC, PDE, cAMP effectors substrates and further scaffolding proteins, provid‐

scaffolding proteins AKAPs and PDEs.

ing spatial and temporal specificity of the cAMP pathway.

**Figure 1.** Roles of cAMP (3'-5' adenosine monophosphate) in differenciated and trans-differentiated vascular smooth muscle cells (VSMC); AC8: adenylyl cyclase 8.
