Parathyroid-induced angiogenesis is VEGF-dependent.
BACKGROUND
Autotransplantation of parathyroid tissue after parathyroidectomy is successful at salvaging parathyroid function. The relatively high success of parathyroid transplantation is thought to be due, in part, to the ability of parathyroid tissue to induce angiogenesis and thus recruit a new vasculature. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor produced by a number of tumors and hypoxic tissues. Using a 3-dimensional intact microvessel angiogenesis system, we evaluated the role of VEGF in the stimulation of angiogenesis by human parathyroid cells.


METHODS
Freshly isolated rat microvessels embedded in a 3-dimensional collagen I matrix were treated with healthy 1-mm(3) fragments of human parathyroid tissue or isolated parathyroid cells. Other gels were supplemented with VEGF(165) or FLT-1 soluble receptor fusion protein to bind VEGF. After 11 days in culture, the gels were stained with Gs-1 lectin, a marker for rat endothelium, and linear growth of the microvessels was determined by using image analysis. Parathyroid production of VEGF was determined with reverse transcriptase-polymerase chain reaction.


RESULTS
A significant increase in microvessel growth was seen in parathyroid coculture (8.4 +/- 1.0 mm) versus VEGF(165) supplemented gels (6.2 +/- 0.3 mm, P <.01). VEGF(165) significantly augmented parathyroid-stimulated angiogenesis (13.7 +/- 2.4 mm, P <.05 vs parathyroid alone). Using quantitative reverse transcriptase-polymerase chain reaction, we identified VEGF messenger RNA (mRNA) induction within 1 hour of parathyroid explant, with a 12-fold increase by 24 hours. Treatment of parathyroid cocultures with 0.2 microg/mL FLT-1 soluble receptor protein completely eliminated the parathyroid induction of angiogenesis.


CONCLUSIONS
Parathyroid tissue expresses low levels of VEGF mRNA, which is significantly upregulated on explantation. Furthermore, the increased VEGF expression is essential to drive parathyroid-induced angiogenesis in our model. However, our data suggests that other parathyroid-produced factors are involved in mediating parathyroid-induced angiogenesis.
Carter
W B
WB
Department of Surgery, Eastern Virginia Medical School, Norfolk, VA, USA.
Uy
K
K
Ward
M D
MD
Hoying
J B
JB
D000273:Adipose Tissue / Q000098:blood supply; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D016228:Endothelial Growth Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D004822:Epididymis; D005786:Gene Expression Regulation; D006801:Humans; D008222:Lymphokines / Q000187:drug effects / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D010280:Parathyroid Glands / Q000166:cytology / Q000502:physiology*; D016105:Parathyroidectomy; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; D019098:Telomerase