Enhanced angiogenesis and increased cardiac perfusion after myocardial infarction in protein tyrosine phosphatase 1B-deficient mice

FASEB J. 2014 Aug;28(8):3351-61. doi: 10.1096/fj.13-245753. Epub 2014 Apr 23.


The protein tyrosine phosphatase 1B (PTP1B) modulates tyrosine kinase receptors, among which is the vascular endothelial growth factor receptor type 2 (VEGFR2), a key component of angiogenesis. Because PTP1B deficiency in mice improves left ventricular (LV) function 2 mo after myocardial infarction (MI), we hypothesized that enhanced angiogenesis early after MI via activated VEGFR2 contributes to this improvement. At 3 d after MI, capillary density was increased at the infarct border of PTP1B(-/-) mice [+7±2% vs. wild-type (WT), P = 0.05]. This was associated with increased extracellular signal-regulated kinase 2 phosphorylation and VEGFR2 activation (i.e., phosphorylated-Src/Src/VEGFR2 and dissociation of endothelial VEGFR2/VE-cadherin), together with higher infiltration of proangiogenic M2 macrophages within unchanged overall infiltration. In vitro, we showed that PTP1B inhibition or silencing using RNA interference increased VEGF-induced migration and proliferation of mouse heart microvascular endothelial cells as well as fibroblast growth factor (FGF)-induced proliferation of rat aortic smooth muscle cells. At 8 d after MI in PTP1B(-/-) mice, increased LV capillary density (+21±3% vs. WT; P<0.05) and an increased number of small diameter arteries (15-50 μm) were likely to participate in increased LV perfusion assessed by magnetic resonance imaging and improved LV compliance, indicating reduced diastolic dysfunction. In conclusion, PTP1B deficiency reduces MI-induced heart failure promptly after ischemia by enhancing angiogenesis, myocardial perfusion, and diastolic function.

Keywords: cytokines; growth factors; vascular growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta
  • Arterioles / physiopathology
  • Capillaries / physiopathology
  • Cardiotonic Agents / pharmacology
  • Cell Division
  • Cell Movement
  • Cells, Cultured
  • Coronary Circulation / physiology*
  • Diastole
  • Endothelial Cells / pathology
  • Heart Failure / etiology
  • Heart Failure / physiopathology
  • Heart Failure / prevention & control
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Molecular Targeted Therapy
  • Myocardial Infarction / complications
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / physiopathology*
  • Myocytes, Smooth Muscle / cytology
  • Neovascularization, Physiologic / physiology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / deficiency
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / physiology
  • RNA Interference
  • Rats
  • Signal Transduction
  • Vascular Endothelial Growth Factor Receptor-2 / physiology
  • Ventricular Dysfunction, Left / etiology
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Remodeling


  • Cardiotonic Agents
  • Vascular Endothelial Growth Factor Receptor-2
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse