Ending Restenosis: Inhibition of Vascular Smooth Muscle Cell Proliferation by cAMP

Abstract

Increased vascular smooth muscle cell (VSMC) proliferation contributes towards restenosis after angioplasty, vein graft intimal thickening and atherogenesis. The second messenger 3′ 5′ cyclic adenosine monophosphate (cAMP) plays an important role in maintaining VSMC quiescence in healthy vessels and repressing VSMC proliferation during resolution of vascular injury. Although the anti-mitogenic properties of cAMP in VSMC have been recognised for many years, it is only recently that we gained a detailed understanding of the underlying signalling mechanisms. Stimuli that elevate cAMP in VSMC inhibit G1-S phase cell cycle progression by inhibiting expression of cyclins and preventing S-Phase Kinase Associated Protein-2 (Skp2-mediated degradation of cyclin-dependent kinase inhibitors. Early studies implicated inhibition of MAPK signalling, although this does not fully explain the anti-mitogenic effects of cAMP. The cAMP effectors, Protein Kinase A (PKA) and Exchange Protein Activated by cAMP (EPAC) act together to inhibit VSMC proliferation by inducing Cyclic-AMP Response Element Binding protein (CREB) activity and inhibiting members of the RhoGTPases, which results in remodelling of the actin cytoskeleton. Cyclic-AMP induced actin remodelling controls proliferation by modulating the activity of Serum Response Factor (SRF) and TEA Domain Transcription Factors (TEAD), which regulate expression of genes required for proliferation. Here we review recent research characterising these mechanisms, highlighting novel drug targets that may allow the anti-mitogenic properties of cAMP to be harnessed therapeutically to limit restenosis.

Nitric oxide activates AMPK by modulating PDE3A in human pulmonary artery smooth muscle cells

“…Although our data demonstrate that PDE3 inhibition prevented NO-induced AMPK activation, pretreatment with the nonselective PDE3 inhibitor milrinone also decreased hPASMC proliferation, similar to milrinone treatment alone ( Figure 6). Previous in vitro studies have shown that decreasing cAMP degradation (PDE inhibitors) or increasing cAMP synthesis (adenylyl cyclase activator) significantly inhibits vascular smooth muscle cell proliferation (Chen, Calvert, Meng, & Nelin, 2012;Smith, Newby, & Bond, 2019). Thus, we speculate that the decreased proliferation observed with milrinone treatment is likely due to the increase in cAMP levels (Figure 1e) and is consistent with previous reports demonstrating that nonselective PDE3 inhibition decreases systemic and pulmonary vascular SMC proliferation (Chen et al, 2012;Kondo, Umemura, Miyaji, & Nakashima, 1999;Phillips, Long, Wilkins, & Morrell, 2005).…”

Activation of overexpressed glucagon‐like peptide‐1 receptor attenuates prostate cancer growth by inhibiting cell cycle progression

“…In the present study, the key mechanism by which Ex-4 attenuates ALVA-41 cell proliferation through GLP-1R activation could be upregulation of cAMP level, because forskolin also decreased ALVA-41 cell proliferation. In fact, cAMP activates SKP2 expression and attenuates cell proliferation in VSMCs 3,33 . SKP2 induction by cAMP increased by GLP-1R signaling could be one of the mechanisms by which GLP-1 attenuates prostate cancer growth, similar to ERK inhibition 10 .…”

Special Issue on “New Advances in Cyclic AMP Signalling”—An Editorial Overview

“…For example, the manuscript, entitled “Epac1 protein: pharmacological modulators, cardiac signalosome and pathophysiology”, by Bouvet et al [ 35 ] presents an overview of the recent advances in pharmacological tools to target EPAC signaling and it illustrates the role of EAPC1 in cardiomyocytes and how dysregulation of EPAC signaling may contribute to the development of cardiac disease. Indeed, the review by Smith et al [ 8 ] details how PKA and EPAC1 suppresses vascular smooth muscle cell proliferation through cytoskeleton remodelling and proliferation-associated gene expression through TEAD transcription factors, highlighting further potential drug targets for the treatment of restenosis after angioplasty, vein graft intimal thickening, and atherosclerosis [ 8 ]. These new cyclic AMP-dependent transcription factor pathways are complemented by new findings from the Yarwood lab that demonstrate that EPAC1 and C/EBP and c-Jun transcription factors mediate cyclic AMP-regulated inflammatory gene expression in vascular endothelial cells, which also provides a new drug-able route for the treatment of inflammation that is associated with vascular disease [ 36 ].…”

“…Biological processes mediated by cyclic AMP include metabolism, gene regulation, and immune function and its deregulation is associated with many pathologies, including metabolic, psychiatric, cardiovascular, pulmonary, and inflammatory disorders, as well as certain cancers. For example, key studies in this here concentrate on regulatory roles for cyclic AMP in cardiac fibrosis [ 6 ], hepatocellular carcinoma [ 7 ], restenosis [ 8 ], and chronic obstructive pulmonary disorder (COPD) [ 5 ]. In addition, Negreiros-Lima et al described a new role for cyclic AMP in regulating important functions of monocytes/macrophages during the resolution of inflammation.…”