Spexin as a modulator of luteal homeostasis: in vitro effect on the regulation of markers of angiogenesis, cell survival and autophagy pathways in porcine corpus luteum

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The corpus luteum (CL) is a transient endocrine gland responsible for progesterone synthesis, and its proper function depends on coordinated regulation of angiogenesis, proliferation, apoptosis, and autophagy. Spexin (SPX), a pleiotropic neuropeptide/adipokine acting via galanin receptors (GALR2/GALR3), has recently been implicated in CL physiology; however, its role in luteal-cell survival and vascular regulation remains unclear. In this study porcine luteal cells were treated with SPX (0.1-10 nM) for 24 and 48h. Angiogenic, apoptotic, and autophagy-related markers were evaluated at the mRNA and protein levels, together with cell viability, proliferation and autophagosome formation. The role of signalling pathways involved in SPX action was examined using pharmacological inhibition of GALR2 receptor and MAP3/1, AKT, and STAT3 kinases. The results demonstrated that SPX increased VEGFA secretion and VEGFA mRNA expression, elevated VEGFR1, and decreased FGFR2 protein and reduced iNOS secretion. Luteal-cell viability decreased after 48 h at 10 nM of SPX, and proliferation declined at all doses, with reduced PCNA protein at doses 0.1 and 1 nM. Apoptotic signalling was enhanced, as shown by increased BAX and CASP3 and decreased BCL2 mRNA and protein levels. SPX also stimulated autophagosome formation, increased beclin-1 level and elevated LC3 protein. These effects on VEGFA, BECN1 mRNA expression and luteal cell viability were mediated via GALR2, MAP3/1, AKT, and STAT3 pathways. Collectively, these findings identify SPX as a novel regulator of key processes involved in CL remodeling and luteal homeostasis, including markers of angiogenesis, apoptosis, and autophagy.