Increased levels of cAMP are translated into cellular responses by cAMP effectors. The αs of the Gs subtype activates adenylyl cyclases (AC) witch catalyzes the synthesis of cAMP from ATP. Both the α and the βγ subunits can then activate or inhibit distinct intracellular signalling cascades. The ligand-bound GPCR catalyzes the exchange of GDP for GTP on the α-subunit of the coupled heterotrimeric G protein, which results in the activation of the α-subunit and its dissociation from the βγ dimer. The c-AMP signalling pathway begins with the release of cAMP into the cell which is mostly initiated by the activation of G-protein coupled receptors (GPCRs) by several different hormones and neurotransmitters. After a presentation of the cAMP signalling pathway, this chapter discusses data demonstrating the diversity of roles of cAMP in differentiated and transdifferentiated VSMCs. 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. Final cAMP effect depends on which isoforms of these proteins are expressed. Adenylyl cyclases (AC), phosphodiesterases (PDE) and the scaffolding proteins A kinase anchored proteins (AKAPs) play a determinant role in cAMP compartmentalization. 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. 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. Alternatively, in differentiated VSMCs, cAMP induces relaxation, expression of contractile proteins, maintenance of a low proliferation rate and can stimulate or inhibit apoptosis ( Figure 1). Indeed, in trans-differentiated VSMCs, cAMP has dual opposite effects on migration and inflammation and stops cell proliferation. 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. Signalling pathways involved in VSMC trans-differentiation are diverse. 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. ![]() This phenotypic transition, also called the trans-differentiation process, plays a critical role in pathological vascular remodellings such as atherosclerosis, post-angioplasty restenosis, bypass vein graft failure, and cardiac allograft vasculopathy. 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 is mainly characterized by the loss of contractility and the acquisition of a proliferative, migratory and synthetic phenotype. VSMC undergo significant phenotypic modulation following vascular injuries including hypoxia, oxidative stress and mechanical injury. ![]() 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. Protein kinase A is an enzyme that is found in different types of cells and has a different target protein depending on which type of cell it is found in.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. ![]() Transcription and Translation in Prokaryotes. ![]()
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