Phenylephrine induces elevated RhoA activation and smooth muscle α-actin expression in Pkd2+/-vascular smooth muscle cells

Hui Du, Xiangling Wang, Jun Wu, Qi Qian

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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, Ca2+independent vasocontraction and (2) smooth muscle α-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.

Original languageEnglish (US)
Pages (from-to)37-42
Number of pages6
JournalHypertension Research
Volume33
Issue number1
DOIs
StatePublished - Jan 1 2010

Keywords

  • MRTF
  • Polycystin
  • RhoA
  • SM alpha;-actin
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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