Lipid phosphate phosphatase 3 negatively regulates smooth muscle cell phenotypic modulation to limit intimal hyperplasia

Arterioscler Thromb Vasc Biol. 2013 Jan;33(1):52-9. doi: 10.1161/ATVBAHA.112.300527. Epub 2012 Oct 25.


Objective: The lipid phosphate phosphatase 3 (LPP3) degrades bioactive lysophospholipids, including lysophosphatidic acid and sphingosine-1-phosphate, and thereby terminates their signaling effects. Although emerging evidence links lysophosphatidic acid to atherosclerosis and vascular injury responses, little is known about the role of vascular LPP3. The goal of this study was to determine the role of LPP3 in the development of vascular neointima formation and smooth muscle cells (SMC) responses.

Methods and results: We report that LPP3 is expressed in vascular SMC after experimental arterial injury. Using gain- and loss-of-function approaches, we establish that a major function of LPP3 in isolated SMC cells is to attenuate proliferation (extracellular signal-regulated kinases) activity, Rho activation, and migration in response to serum and lysophosphatidic acid. These effects are at least partially a consequence of LPP3-catalyzed lysophosphatidic acid hydrolysis. Mice with selective inactivation of LPP3 in SMC display an exaggerated neointimal response to injury.

Conclusions: Our observations suggest that LPP3 serves as an intrinsic negative regulator of SMC phenotypic modulation and inflammation after vascular injury, in part, by regulating lysophospholipid signaling. These findings may provide a mechanistic link to explain the association between a PPAP2B polymorphism and coronary artery disease risk.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carotid Artery Injuries / enzymology
  • Carotid Artery Injuries / genetics
  • Carotid Artery Injuries / pathology
  • Carotid Artery Injuries / prevention & control*
  • Carotid Artery, Common / enzymology
  • Carotid Artery, Common / pathology
  • Cell Movement
  • Cell Proliferation*
  • Disease Models, Animal
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation
  • Genotype
  • HEK293 Cells
  • Humans
  • Hydrolysis
  • Hyperplasia
  • Lysophospholipids / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / pathology
  • Neointima
  • Phenotype
  • Phosphatidate Phosphatase / deficiency
  • Phosphatidate Phosphatase / genetics
  • Phosphatidate Phosphatase / metabolism*
  • Signal Transduction
  • Time Factors
  • Transfection
  • rho-Associated Kinases / metabolism


  • Lysophospholipids
  • rho-Associated Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • PLPP3 protein, human
  • Phosphatidate Phosphatase
  • Plpp3 protein, mouse
  • lysophosphatidic acid