Heparin impairs angiogenic signaling and compensatory lung growth after left pneumonectomy

Angiogenesis. 2018 Nov;21(4):837-848. doi: 10.1007/s10456-018-9628-3. Epub 2018 Jun 28.


Children with hypoplastic lung diseases, such as congenital diaphragmatic hernia, can require life support via extracorporeal membrane oxygenation and systemic anticoagulation, usually in the form of heparin. The role of heparin in angiogenesis and organ growth is inconclusive, with conflicting data reported in the literature. This study aimed to investigate the effects of heparin on lung growth in a model of compensatory lung growth (CLG). Compared to the absence of heparin, treatment with heparin decreased the vascular endothelial growth factor (VEGF)-mediated activation of VEGFR2 and mitogenic effect on human lung microvascular endothelial cells in vitro. Compared to non-heparinized controls, heparinized mice demonstrated impaired pulmonary mechanics, decreased respiratory volumes and flows, and reduced activity levels after left pneumonectomy. They also had lower lung volume, pulmonary septal surface area and alveolar density on morphometric analyses. Lungs of heparinized mice displayed decreased phosphorylation of VEGFR2 compared to the control group, with consequential downstream reduction in markers of cellular proliferation and survival. The use of bivalirudin, an alternative anticoagulant that does not interact with VEGF, preserved lung growth and pulmonary mechanics. These results demonstrated that heparin impairs CLG by reducing VEGFR2 activation. These findings raise concern for the clinical use of heparin in the setting of organ growth or regeneration.

Keywords: Bivalirudin; Compensatory lung growth; Heparin; Pneumonectomy; Vascular endothelial growth factor.

Publication types

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

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Heparin / pharmacology*
  • Hirudins / pharmacology
  • Humans
  • Lung / growth & development*
  • Lung / pathology
  • Male
  • Mice
  • Peptide Fragments / pharmacology
  • Pneumonectomy*
  • Recombinant Proteins / pharmacology
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*


  • Hirudins
  • Peptide Fragments
  • Recombinant Proteins
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Heparin
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2
  • bivalirudin