Abstract
Background: In this study, we investigated the mechanism of Rho GTPases signaling on Ang II-mediated cell migration and dedifferentiation in human aortic vascular smooth muscle cells (HA-VSMCs) and an Ang II-infusion mouse model. Methods: Cells were pretreated with different inhibitors or Ang II. Cell migration was detected by Wound healing and Transwell assay. Mice were treated with Ad-RhoA-shRNA virus or Irbesartan or fasudil and then infused with Ang II. Results: Ang II treatment induced HA-VSMCs migration in a dose- and time-dependent manner and reduced the expression of VSMC contractile proteins. These effects were significantly suppressed by the inhibition of Ang II type 1 receptor (AT1 receptor), RhoA, and Rho-associated kinase (ROCK). Furthermore, Ang II treatment promoted the activation of RhoA and ROCK, which was reduced by AT1 receptor inhibition. Meanwhile, Ang II treatment induced F-actin polymerization, which was inhibited after ROCK inhibition. In mice, Ang II infusion increased VSMC migration into the neointima and reduced VSMC differentiation proteins levels, and these effects were shown to be dependent on AT1 receptor and RhoA/ROCK pathway. Conclusion: This study reveals a novel mechanism by which Ang II regulates RhoA/ROCK signaling and actin polymerization via AT1 receptor and then affects VSMC dedifferentiation.
Highlights
The main function of vascular smooth muscle cells (VSMCs) is contraction
It is noted that VSMCs switch from the contractile phenotype toward proliferative, migratory, and/or inflammatory phenotypes under the presence of PDGF-BB [23], insulin-like growth factors (IGFs) [3], interferon gamma (IFN-γ) [24], angiotensin II (Ang II) [19,20,25] or in spontaneously hypertensive rats (SHR) [26]
The effects of different Rho GTPase members on Ang II-mediated smooth muscle migration and dedifferentiation in human cell lines and the mechanisms behind these effects are not well understood, though we recently revealed a novel mechanism by which Ang II regulates VSMC proliferation by Rho-specific guanine nucleotide dissociation inhibitor (RhoGDI) protein stability [12]
Summary
The main function of vascular smooth muscle cells (VSMCs) is contraction. VSMCs differentiation requires the expression of several contractile proteins; including smooth muscle α-actin (ACTA2), smooth muscle myosin heavy chain (MYH11), transgelin (TAGLN), and smoothelin [1]. Results: Ang II treatment induced HA-VSMCs migration in a dose- and time-dependent manner and reduced the expression of VSMC contractile proteins. These effects were significantly suppressed by the inhibition of Ang II type 1 receptor (AT1 receptor), RhoA, and Rho-associated kinase (ROCK). Ang II infusion increased VSMC migration into the neointima and reduced VSMC differentiation proteins levels, and these effects were shown to be dependent on AT1 receptor and RhoA/ROCK pathway. Conclusion: This study reveals a novel mechanism by which Ang II regulates RhoA/ROCK signaling and actin polymerization via AT1 receptor and affects VSMC dedifferentiation
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