Cysteine-rich angiogenic inducer 61 (CYR61), an angiogenic factor whose expression is decreased in fibroids. The aim of the present study was to determine if CYR61 secretion in smooth muscle cells (SMCs) is regulated by hypoxia and through the endothelin A (ET) receptor. SMCs from fibroids (fSMC) and the adjacent myometrium smooth muscle cells (mSMCs) were extracted from ten women undergoing hysterectomy for uterine fibroids and cultured with or without 1.0 µM of an ET receptor antagonist for 24 h under either normal or hypoxic oxygen conditions. Cellular secretion of endothelin-1 (ET-1) and CYR61 were measured via enzyme linked immunosorbent assay in the cell culture media. SMCs were collected to determine cell proliferation and CYR61 protein expression via Western blot. ET-1 secretion was significantly increased in fSMC and was decreased with blockade of the ET receptor under both normoxia (=0.0004) and hypoxia (=0.008). CYR61 expression was decreased in fSMCs and significantly increased with blockade of the ET receptor under hypoxia (=0.04). Cell proliferation decreased with ET blockade under normoxia (=0.0001) and hypoxia (=0.001). These results suggest that suppression of CYR61 secretion in fSMC is regulated by the ET-1 and that blockade with ET could be considered for a future treatment option.