Thyroid hormone receptor blockade by amiodarone disrupts angiogenesis via VEGFα, WNT7A, BMP, and PI3K/AKT pathways in chick embryo vascular development.

BackgroundThyroid hormones (TH) play critical roles in embryonic vascular development, yet their precise molecular contributions remain inadequately defined. This study investigates how pharmacological blockade of thyroid hormone receptors (TR) by amiodarone disrupts angiogenesis and associated molecular signaling pathways in chick embryos.ResultsAmiodarone-treated embryos exhibited notable morphological defects, including hematomas, anophthalmia, ventral wall defects, and limb anomalies, primarily affecting lateral plate mesoderm-derived tissues. Chorioallantoic membrane analysis revealed significant reductions in vessel density, branching, and total vessel length, along with increased lacunarity, indicating impaired angiogenesis. Molecular profiling showed consistent down-regulation of key angiogenic regulators such as VEGFα, WNT7A, BMP2/6, and phosphatidylinositol 3-kinase/ Ak strain transforming (PI3K/AKT) at both transcript and protein levels. In silico docking confirmed strong TRα and TRβ binding, while deiodinase activity assays and western blotting demonstrated impaired thyroxine-to-triiodothyronine (T3) conversion and reduced T3 levels, confirming systemic hypothyroidism and disrupted thyroid hormone signaling.ConclusionOur findings underscore the essential role of thyroid hormone signaling in embryonic angiogenesis. Disruption of TR activation by amiodarone significantly impairs vascular formation through coordinated suppression of Vascular endothelial growth factor alpha (VEGFα), WNT7A, bone morphogenetic proteins, and PI3K/AKT pathways. These insights enhance our understanding of TH-related developmental disorders and may guide therapeutic strategies for managing vascular dysfunctions associated with impaired thyroid signaling.