CONTEXT: TSH, which acts via specific cell membrane TSH receptors (TSHR), is regarded as a thyroid-specific growth factor. Recently, the presence of TSHR has been reported in extrathyroid tissues, but the role of TSH in nonthyroid tissue is unknown. OBJECTIVE: Our objective was to study the direct effect of TSH on angiogenesis in a human dermal microvascular endothelial cell line (HMEC-1). Parallel experiments were conducted with human primary cardiac microvascular endothelial cells (HMVEC-C). DESIGN: TSHR in HMEC-1 was measured by immunofluorescence, Western blot, and RT-PCR and its functional activity by variation of intracellular cAMP concentrations. The expression of some angiogenic genes and angiogenic signaling pathways was also evaluated after TSH treatment. Assays of cell proliferation and capillary network formation on collagen or Matrigel were performed in HMEC-1 cells and HMVEC-C. RESULTS: We showed the presence of TSHR in HMEC-1 cells. Increased intracellular cAMP concentrations after TSH treatment indicated the TSHR to be functional. TSH enhanced proliferation and stimulated capillary network formation in HMEC-1, whereas antibodies against vascular endothelial growth factor (VEGF) and TSHR abolished this effect. TSH increased AAMP, VEGF, and eNOS expression. TSH induced phosphorylation of protein kinase S6K1, whereas TSHR blocking antibodies inhibited the phosphorylation of the protein kinase S6K1. A similar effect of TSH on capillary network formation was observed in HMVEC-C. CONCLUSION: Our findings provide strong evidence for a direct effect of TSH on angiogenesis through its receptor, via cAMP-mammalian target of rapamycin signaling and indicate that this effect is VEGF dependent