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 avb3, but the precise signaling pathway is still not very clear. Recently, studies have shown that protein kinase D (PKD) regulates the recycling of integrin avb3, 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 avb3/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 analyzedbyreal-time PCR.Our results showedthat T4 (100 nmol/l) stimulatedthemigrationand 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 mmol/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 avb3/PKD/HDAC5 signaling pathway, which plays an important role in angiogenesis. © 2014 Society for Endocrinology.