Stimulatory effects of thyroid hormone on brain angiogenesis in vivo and in vitro.
Thyroid hormone is critical for the proper development of the central nervous system. However, the specific role of thyroid hormone on brain angiogenesis remains poorly understood. Treatment of rats from birth to postnatal day 21 (P21) with propylthiouracil (PTU), a reversible blocker of triiodothyronine (T3) synthesis, resulted in decreased brain angiogenesis, as indicated by reduced complexity and density of microvessels. However, when PTU was withdrawn at P22, these parameters were fully recovered by P90. These changes were paralleled by an altered expression of vascular endothelial growth factor A (Vegfa) and basic fibroblast growth factor (Fgf2). Physiologic concentrations of T3 and thyroxine (T4) stimulated proliferation and tubulogenesis of rat brain-derived endothelial (RBE4) cells in vitro. Protein and mRNA levels of VEGF-A and FGF-2 increased after T3 stimulation of RBE4 cells. The thyroid hormone receptor blocker NH-3 abolished T3-induced Fgf2 and Vegfa upregulation, indicating a receptor-mediated effect. Thyroid hormone inhibited the apoptosis in RBE4 cells and altered mRNA levels of apoptosis-related genes, namely Bcl2 and Bad. The present results show that thyroid hormone has a substantial impact on vasculature development in the brain. Pathologically altered vascularization could, therefore, be a contributing factor to the neurologic deficits induced by thyroid hormone deficiency.
Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
Liqun
L
Zhang
Christiana Marie
CM
Cooper-Kuhn
Ulf
U
Nannmark
Klas
K
Blomgren
Hans Georg
HG
Kuhn
D000818:Animals; D013956:Antithyroid Agents / Q000633:toxicity; D001921:Brain / Q000098:blood supply* / Q000254:growth & development*; D005455:Fluorescent Antibody Technique; D007037:Hypothyroidism / Q000139:chemically induced / Q000503:physiopathology; D007150:Immunohistochemistry; D046529:Microscopy, Electron, Transmission; D055806:Microvessels / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011441:Propylthiouracil / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013974:Thyroxine / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism*
D013956:Antithyroid Agents; D014284:Triiodothyronine; D011441:Propylthiouracil; D013974:Thyroxine