MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury

  1. Mei Xin1,
  2. Eric M. Small1,
  3. Lillian B. Sutherland1,
  4. Xiaoxia Qi1,
  5. John McAnally1,
  6. Craig F. Plato2,
  7. James A. Richardson1,3,
  8. Rhonda Bassel-Duby1 and
  9. Eric N. Olson1,4
  1. 1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  2. 2Gilead Colorado, Inc., Boulder, Colorado 80301, USA;
  3. 3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    Abstract

    Vascular injury triggers dedifferentiation and cytoskeletal remodeling of smooth muscle cells (SMCs), culminating in vessel occlusion. Serum response factor (SRF) and its coactivator, myocardin, play a central role in the control of smooth muscle phenotypes by regulating the expression of cytoskeletal genes. We show that SRF and myocardin regulate a cardiovascular-specific microRNA (miRNA) cluster encoding miR-143 and miR-145. To assess the functions of these miRNAs in vivo, we systematically deleted them singly and in combination in mice. Mice lacking both miR-143 and miR-145 are viable and do not display overt abnormalities in smooth muscle differentiation, although they show a significant reduction in blood pressure due to reduced vascular tone. Remarkably, however, neointima formation in response to vascular injury is profoundly impeded in mice lacking these miRNAs, due to disarray of actin stress fibers and diminished migratory activity of SMCs. These abnormalities reflect the regulation of a cadre of modulators of SRF activity and actin dynamics by miR-143 and miR-145. Thus, miR-143 and miR-145 act as integral components of the regulatory network whereby SRF controls cytoskeletal remodeling and phenotypic switching of SMCs during vascular disease.

    Keywords

    Footnotes

    | Table of Contents

    Life Science Alliance