title: N-Cadherin Induction by ECM Stiffness and FAK Overrides the Spreading Requirement for Proliferation of Vascular Smooth Muscle Cells.
abstract: In contrast to the accepted pro-proliferative effect of cell-matrix adhesion, the proliferative effect of cadherin-mediated cell-cell adhesion remains unresolved. Here, we studied the effect of N-cadherin on cell proliferation in the vasculature. We show that N-cadherin is induced in smooth muscle cells (SMCs) in response to vascular injury, an in vivo model of tissue stiffening and proliferation. Complementary experiments performed with deformable substrata demonstrated that stiffness-mediated activation of a focal adhesion kinase (FAK)-p130Cas-Rac signaling pathway induces N-cadherin. Additionally, by culturing paired and unpaired SMCs on microfabricated adhesive islands of different areas, we found that N-cadherin relaxes the spreading requirement for SMC proliferation. In vivo SMC deletion of N-cadherin strongly reduced injury-induced cycling. Finally, SMC-specific deletion of FAK inhibited proliferation after vascular injury, and this was accompanied by reduced induction of N-cadherin. Thus, a stiffness- and FAK-dependent induction of N-cadherin connects cell-matrix to cell-cell adhesion and regulates the degree of cell spreading needed for cycling.
authors.affiliation: Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Keeley L
authors.initials: KL
authors.lastname: Mui
authors.affiliation: Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Bae
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Gao
authors.affiliation: Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Shu-Lin
authors.initials: SL
authors.lastname: Liu
authors.affiliation: Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Medicine, Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Radice
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA. Electronic address: chencs@bu.edu.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: assoian@mail.med.upenn.edu.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Assoian