title: Thyroid hormone induced angiogenesis through the integrin αvβ3/protein kinase D/histone deacetylase 5 signaling pathway.
abstract: Thyroid hormone is reported to induce angiogenesis, which is mediated by the membrane receptor integrin αvβ3, but the precise signaling pathway is still not very clear. Recently, studies have shown that protein kinase D (PKD) regulates the recycling of integrin αvβ3, which is required for cell migration. Moreover, phosphorylated PKD stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in endothelial cells. As a potent pro-angiogenic growth factor, basic fibroblast growth factor (bFGF (FGF2)) is a downstream target gene of HDAC5. Therefore, we examined the hypothesis that a novel signaling pathway through integrin αvβ3/PKD/HDAC5 might contribute to thyroxine (T4)-induced angiogenesis. We selected human umbilical vein endothelial cells (HUVECs) for treatment. Angiogenesis was assessed using wound-healing and tubulogenesis assays. Signaling molecules, including phosphorylated PKD and HDAC5, were measured by western blotting. bFGF mRNA was analyzed by real-time PCR. Our results showed that T4 (100 nmol/l) stimulated the migration and formation of tube-like structures of HUVECs, whereas tetraiodothyroacetic acid (Tetrac, 100 nmol/l) inhibited T4-induced cell migration. Importantly, T4 promoted the phosphorylation of PKD and HDAC5. These effects were inhibited respectively by Tetrac, PKC inhibitor (2.5 μmol/l) and PKD siRNA. Meanwhile, T4 could promote the cytoplasmic accumulation of phosphorylated HDAC5 in HUVECs. In addition, bFGF mRNA expression in HUVECs significantly increased within 2 h of T4 treatment, but was decreased by Tetrac. Our findings indicate that T4 increases the expression of bFGF mRNA via the integrin αvβ3/PKD/HDAC5 signaling pathway, which plays an important role in angiogenesis.
authors.affiliation: Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, 300070 Tianjin, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Nan
authors.initials: N
authors.lastname: Zheng
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Shi
authors.forename: Jihong
authors.initials: J
authors.lastname: Yuan
authors.forename: Lanying
authors.initials: L
authors.lastname: Li
mesh_terms: D021581:Active Transport, Cell Nucleus; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D006655:Histone Deacetylases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D015398:Signal Transduction; D013974:Thyroxine / Q000031:analogs & derivatives / Q000494:pharmacology*; D014945:Wound Healing / Q000502:physiology
chemical_list: D039302:Integrin alphaVbeta3; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016222:Fibroblast Growth Factor 2; C089212:protein kinase D; D011493:Protein Kinase C; C404500:HDAC5 protein, human; D006655:Histone Deacetylases; C011126:tetraiodothyroacetic acid; D013974:Thyroxine
keywords: angiogenesis; basic fibroblast growth factor; histone deacetylase 5; human umbilical vein endothelial cells; integrin αvβ3; protein kinase D; thyroid hormone