Akt Controls Vascular Smooth Muscle Cell Proliferation In Vitro and In Vivo by Delaying G1/S Exit

Abstract

Abstract-Constitutive activation of serine/threonine kinase Akt causes uncontrolled cell-cycle progression in different cell types and in malignancy. To investigate how Akt activation modulates cell-cycle progression in vascular smooth muscle cells (SMCs) in vitro and in the intact animal, we inhibited Akt-dependent signaling by adenovirus-mediated transfection of a dominant-negative Akt mutant (AA-Akt). We observed reduced proliferation rate (PϽ0.01), DNA synthesis (PϽ0.01), and a significant arrest in G1/S exit (PϽ0.01) both in vitro in response to serum stimulation and in vivo after vascular injury. In vivo transfection of the balloon-injured vessel with AA-Akt reduced SMC proliferation, resulting in decreased neointima compared with control virus (PϽ0.01). These effects were at least in part modulated, both in vitro and in vivo, by increased p21 Cip1 expression, as demonstrated by lack of effect of AA-Akt on cell proliferation in p21 Ϫ/Ϫ mouse SMCs. In conclusion, this study demonstrates that Akt-dependent signaling enhances cell-cycle progression of nontransformed SMCs in vitro and in response to vascular injury in the intact animal. These results suggest a role for Akt signaling in modulating the response of normal tissues to stress and the response of the arterial wall to acute and possibly repetitive injuries that ultimately contribute to restenosis and atherosclerosis.

Resistin Promotes Smooth Muscle Cell Proliferation Through Activation of Extracellular Signal–Regulated Kinase 1/2 and Phosphatidylinositol 3-Kinase Pathways

“…38 In a recent study, Akt was found to influence cell-cycle progression of SMCs both in vitro and in vivo. 39 In the present study we also found that the PI3K-Akt pathway was involved in resistin-induced HASMC proliferation, and we demonstrated that the use of a specific inhibitor of this pathway, LY294002, dramatically reduced the proliferation after resistin stimulation.…”

Tollip Negatively Regulates Vascular Smooth Muscle Cell–Mediated Neointima Formation by Suppressing Akt‐Dependent Signaling

“…Because Akt plays a critical role in the pathophysiology of VSMC remodeling and the capacity of Tollip to modulate adverse cardiac remodeling through Akt‐dependent pathways have been established,8, 9, 10, 22, 23 we hypothesized that Akt might also be required for the regulatory effects of Tollip on neointima formation. Western blotting was then performed to delineate the expression and phosphorylation of Akt and its downstream molecules, including GSK3β and FOXO3A, in LCAs from each group.…”

“…As a well‐established signaling cascade that participates in intimal hyperplasia, Akt signaling is also a downstream pathway of Tollip in cardiovascular disease 8, 9, 10, 22, 23. Therefore, we investigated the status of the Akt‐dependent signaling pathway in response to vascular injury.…”

“…Genetic manipulation of Akt1 or Akt2 in mice or VSMCs has revealed that Akt1 contributes to VSMC proliferation and migration, whereas Akt2 is necessary for the inhibition of VSMC phenotypic switching, migration, and proliferation 30, 35, 36, 37. Alternatively, numerous studies have shown that Akt activation triggered by vascular injury and PDGF‐BB treatment leads to VSMC migration and proliferation, whereas other studies have elucidated the opposite effect following insulin‐like growth factor–induced Akt activation 22, 23, 30. Therefore, the role of Akt in neointima formation may also depend on the isoform and upstream stressors.…”

A Novel Approach against Vascular Intimal Hyperplasia Through the Suppression of Girdin

“…[4][5][6] Accumulating evidence suggests that the PI3K-Akt pathway and its downstream components also play essential roles in vascular remodeling. [7][8][9][10][11] However, the underlying molecular mechanisms are not completely understood.…”