EPAC in Vascular Smooth Muscle Cells.

Nadine Wehbe,Suzanne Awni Nasser,Elias Baydoun,Ali H. Eid,Rabah Iratni,Ahmed F. El-Yazbi,Alessandra Bitto,Adnan Badran,Firas Kobeissy,Yusra Al-Dhaheri

doi:10.3390/ijms21145160

Abstract

Vascular smooth muscle cells (VSMCs) are major components of blood vessels. They regulate physiological functions, such as vascular tone and blood flow. Under pathological conditions, VSMCs undergo a remodeling process known as phenotypic switching. During this process, VSMCs lose their contractility and acquire a synthetic phenotype, where they over-proliferate and migrate from the tunica media to the tunica interna, contributing to the occlusion of blood vessels. Since their discovery as effector proteins of cyclic adenosine 3′,5′-monophosphate (cAMP), exchange proteins activated by cAMP (EPACs) have been shown to play vital roles in a plethora of pathways in different cell systems. While extensive research to identify the role of EPAC in the vasculature has been conducted, much remains to be explored to resolve the reported discordance in EPAC’s effects. In this paper, we review the role of EPAC in VSMCs, namely its regulation of the vascular tone and phenotypic switching, with the likely involvement of reactive oxygen species (ROS) in the interplay between EPAC and its targets/effectors.

Highlights

Cyclic adenosine 3,5 -monophosphate is one of the most studied second messengers that play a critical role in intracellular signaling transduction
The intracellular level of cAMP depends on its production by adenylyl cyclase (AC) and its degradation by cAMP phosphodiesterases (PDEs), which catalyze the hydrolysis of cAMP into 5 -adenosine monophosphate (5 -AMP) [14]
We aim to focus on the role of EPAC in Vascular smooth muscle cells (VSMCs), mainly its involvement in the vascular tone and phenotypic switching

Summary

Introduction

Cyclic adenosine 3 ,5 -monophosphate (cAMP) is one of the most studied second messengers that play a critical role in intracellular signaling transduction It controls a wide variety of cellular responses including cell proliferation, migration, differentiation and apoptosis. In addition to ACs and PDEs, the intracellular level of cAMP is regulated by A-kinase anchoring proteins (AKAPs), scaffolding proteins that sequester cAMP and its relevant signaling components into defined subcellular compartments [15] This compartmentalization helps in sustaining localized pools of cAMP to effectively modulate the cellular actions of this second messenger [16,17]. The discovery of EPAC is relatively new; it has been shown to significantly modulate a plethora of pathways in different cell systems It can control key cellular processes, such as cell proliferation, migration and apoptosis [1,3,16,21]. We provide a detailed and critical discussion of the targeted pathways and the underlying mechanisms involved in VSMC remodeling in in vitro and in vivo models of hypertension and neointimal hyperplasia

Genes and Expression

Structure and Activation

Vascular Tone

Concluding Remarks