Vascular endothelial growth factor accelerates compensatory lung growth after unilateral pneumonectomy

Am J Physiol Lung Cell Mol Physiol. 2007 Mar;292(3):L742-7. doi: 10.1152/ajplung.00064.2006. Epub 2006 Nov 22.

Abstract

We hypothesize that compensatory lung growth after unilateral pneumonectomy in a murine model is, in part, angiogenesis dependent and can be altered using angiogenic agents, possibly through regulation of endothelial cell proliferation and apoptosis. Left pneumonectomy was performed in mice. Mice were then treated with proangiogenic factors [vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF)], VEGF receptor antibodies (MF-1, DC101), and VEGF receptor small molecule chemical inhibitors. Lung volume and mass were measured. The lungs were analyzed using immunohistochemistry by CD31 staining, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling, type II pneumocytes staining, and proliferating cell nuclear antigen. Compensatory lung growth was complete by postoperative day 10 and was associated with diffuse apoptosis of endothelial cells and pneumocytes. This process was accelerated by VEGF, such that growth was complete by postoperative day 4 with similar associated apoptosis. bFGF had no effect on lung growth. MF-1 and DC101 had no effect. The VEGF receptor small molecule chemical inhibitors also had no effect. VEGF, but not bFGF, accelerates growth. VEGF receptor inhibitors do not block growth, suggesting that other proangiogenic factors play a role or can compensate for VEGF receptor blockade. Diffuse apoptosis, endothelial cell and pneumocyte, occurs at cessation of both normal compensatory and VEGF-accelerated growth. Angiogenesis modulators may control growth via regulation of endothelial cell proliferation and apoptosis, although the exact relationship between endothelial cells and pneumocytes has yet to be determined. The fact that bFGF did not accelerate growth in our model when it did accelerate regeneration in the liver model suggests that angiogenesis during organ regeneration is regulated in an organ-specific manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blood Vessels / growth & development*
  • Cell Proliferation
  • Endothelial Growth Factors / pharmacology
  • Endothelium, Vascular / cytology*
  • Endothelium, Vascular / metabolism
  • Fibroblast Growth Factor 2 / pharmacology
  • Immunoenzyme Techniques
  • In Situ Nick-End Labeling
  • Lung / blood supply*
  • Lung / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic
  • Pneumonectomy*
  • Regeneration / physiology
  • Vascular Endothelial Growth Factor A / pharmacology*

Substances

  • Endothelial Growth Factors
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Fibroblast Growth Factor 2