| 19893564 |
Du H, Wang X, Wu J, Qian Q: Phenylephrine induces elevated RhoA activation and smooth muscle alpha-actin expression in Pkd2+/- vascular smooth muscle cells. Hypertens Res. 2010 Jan;33(1):37-42. Epub 2009 Nov 6.
The mechanisms underlying vascular complications in autosomal-dominant polycystic kidney disease (ADPKD) have not been fully elucidated. However, molecular components altered in Pkd mutant vascular smooth muscle cells (VSMCs) are gradually being identified. Pkd2 (+/-) arterial smooth muscles show elevated levels of (1) phenylephrine (PE)-induced, Ca (2+)-independent vasocontraction and (2) smooth muscle alpha-actin (SMA) expression. As these two processes are heavily influenced by RhoA signaling and by cellular filamentous-to-globular (F/G)-actin dynamics, we examined PE-induced changes in RhoA activation and the F/G-SMA ratio in wild-type (wt) and Pkd2 (+/-) VSMCs; we further tested the hypothesis that the abnormal response to PE and the resultant elevation in the F/G-SMA ratio contribute to the exuberant SMA expression in Pkd2 (+/-) VSMCs. GTP-RhoA and F/G-SMA in mouse aortic media and primary cultured VSMCs were determined using RhoA activation and in vivo F-to-G-actin assays. Myocardin-related transcription factor-A (MRTF-A) (SMA transcription coactivator) was localized by immunofluorescence, nuclear MRTF-A quantified by western analysis using nuclear extracts and SMA expression by luciferase reporter assay. PE induced a > 3-fold higher RhoA activation in Pkd2 (+/-) than in wt VSMCs and higher levels of downstream p-LIMK and p-cofilin. Moreover, Pkd2 (+/-) VSMCs showed a higher baseline and PE-induced F/G-SMA ratio. The F/G-SMA elevation enhanced nuclear translocation of MRTF-A, which upregulated SMA transcription. In summary, PE-induced RhoA hyperactivation and defects in F-to-G SMA balance likely have a role in the abnormal vasocontraction and SMA expression in Pkd2 (+/-) arteries. These defects could potentially contribute to the genesis of vascular complications in ADPKD, thus providing new areas for further research and therapeutic targeting. |
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