Shp2 in myocytes is essential for cardiovascular and neointima development

J Mol Cell Cardiol. 2019 Dec:137:71-81. doi: 10.1016/j.yjmcc.2019.09.014. Epub 2019 Oct 18.

Abstract

Mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase Shp2, cause Noonan syndrome and LEOPARD syndrome, inherited multifaceted diseases including cardiac and vascular defects. However, the function of Shp2 in blood vessels, especially in vascular smooth muscle cells (VSMCs), remains largely unknown. We generated mice in which Shp2 was specifically deleted in VSMCs and embryonic cardiomyocytes using the SM22α-Cre transgenic mouse line. Conditional Shp2 knockout resulted in massive hemorrhage, cardiovascular defects and embryonic lethality at the late embryonic developmental stage (embryonic date 16.5). The thinning of artery walls in Shp2-knockout embryos was due to decreased VSMC number and reduced extracellular matrix deposition. Myocyte proliferation was decreased in Shp2-knockout arteries and hearts. Importantly, cardiomyocyte-specific Shp2-knockout did not cause similar vascular defects. Shp2 was required for TGFβ1-induced expression of ECM components, including collagens in VSMCs. In addition, collagens were sufficient to promote Shp2-inefficient VSMC proliferation. Finally, Shp2 was deleted in adult mouse VSMCs by using SMMHC-CreERT2 and tamoxifen induction. Shp2 deletion dramatically inhibited the expression of ECM components, proliferation of VSMCs and neointima formation in a carotid artery ligation model. Therefore, Shp2 is required for myocyte proliferation in cardiovascular development and vascular remodeling through TGFβ1-regulated collagen synthesis.

Keywords: Extracellular matrix; Neointima; Proliferation; Shp2; Vascular smooth muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carotid Arteries / drug effects
  • Carotid Arteries / embryology
  • Carotid Arteries / pathology
  • Cell Proliferation / drug effects
  • Collagen / pharmacology
  • Cyclin D1 / metabolism
  • Embryo, Mammalian / pathology
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Female
  • Heart / embryology*
  • Hemorrhage / pathology
  • Integrases / metabolism
  • Male
  • Mice, Knockout
  • Muscle, Smooth, Vascular / pathology
  • Myocardium / pathology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / pathology
  • Neointima / embryology*
  • Neointima / enzymology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / deficiency
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Rats
  • Signal Transduction / drug effects
  • Smad2 Protein / metabolism
  • Transforming Growth Factor beta / metabolism

Substances

  • Smad2 Protein
  • Transforming Growth Factor beta
  • Cyclin D1
  • Collagen
  • Cre recombinase
  • Integrases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse