scholarly journals Vascular Smooth Muscle as a Therapeutic Target in Disease Pathology

10.5772/60878 ◽  
2015 ◽  
Author(s):  
Andrew W. Holt ◽  
David A. Tulis
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Therapeutic Target

Vascular smooth muscle cell proliferation as a therapeutic target. Part 1: molecular targets and pathways

2018 ◽  
Vol 36 (6) ◽  
pp. 1586-1607 ◽  
Author(s):  
Dongdong Wang ◽  
Pavel Uhrin ◽  
Andrei Mocan ◽  
Birgit Waltenberger ◽  
Johannes M. Breuss ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Therapeutic Target ◽  
Molecular Targets ◽  
Smooth Muscle Cell Proliferation

Abstract 445: Beraprost, a Prostacyclin Analogue, Inhibits Human Vascular Smooth Muscle Cell Migration via Activation of Exchange Protein Activated by cAMP (Epac)

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Jenny S McKean ◽  
Derryck Shewan ◽  
George Gibson ◽  
Graeme F Nixon
Keyword(s):  
Smooth Muscle ◽  
Cell Migration ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Therapeutic Target ◽  
Neointimal Hyperplasia ◽  
Prostacyclin Analogue ◽  
Exchange Protein

Following vein grafting, endothelial damage initiates vascular smooth muscle cell (VSMC) migration to the intima leading to neointimal hyperplasia and restenosis. Inhibition of VSMC migration is therefore a therapeutic target to prevent restenosis. Previous studies have shown that cyclic adenosine monophosphate (cAMP) inhibits VSMC migration although the downstream mediators are unknown. This suggests that cyclic AMP-producing agonists, such as the prostacyclin analogue beraprost which binds to prostanoid receptors, could be used as a potential drug against neointimal formation. We hypothesised that prostacyclin analogues inhibit VSMC migration by activating specific cAMP downstream mediators. The aims of this project were to examine the role of cAMP mediators protein kinase A (PKA) and Exchange protein activated by cAMP (Epac) in this inhibitory effect. Saphenous veins were obtained from patients undergoing coronary artery bypass. VSMCs were primary cultured and migration measured using a chemotaxis chamber. Cell migration stimulated by PDGF was significantly inhibited by 68 ± 5% (n=6) in the presence of a therapeutically relevant concentration of beraprost (1 nM). To examine potential mechanisms of this inhibition, selective activators of PKA and Epac were used. Both Epac and PKA activators significantly inhibited migration towards PDGF. However, fluorescence resonance energy transfer using cells transfected with specific probes revealed that 1 nM beraprost only activates Epac and not PKA in VSMCs (n=4). The downstream mechanisms were further investigated. Pulldown assays demonstrated that beraprost-mediated stimulation of Epac produces subsequent activation of the monomeric G-protein Rap1 and ultimately inhibits RhoA-induced cytoskeleton rearrangement required for migration (n=3). Using siRNA to knockdown Rap1, the inhibition of PDGF-induced migration by beraprost in VSMC cells was shown to be dependent on the Rap1 pathway (n=3). In conclusion, the prostacyclin analogue beraprost inhibits VSMC migration via activation of Epac/Rap1. This may provide a new therapeutic target to prevent neointimal hyperplasia.

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