Mitochondrial-targeted MitoQ attenuates PFOS-induced vasoconstriction and cAMP suppression in human placental arteries†.

Perfluorooctanesulfonic acid (PFOS), a persistent environmental pollutant, is elevated in the plasma of preeclamptic women and may contribute to gestational hypertension. However, its direct effects on placental vascular function remain unclear. This study investigated PFOS' impact on vascular reactivity in human placental chorionic plate arteries (CPAs) and evaluated the therapeutic potential of the mitochondrial-targeted antioxidant mitoquinone (MitoQ). CPAs from normotensive pregnancies were treated with PFOS (10 μM) or vehicle for 24 h. Wire myography assessed contractile responses to KCl and endothelin-1 (ET-1), as well as cyclic adenosine monophosphate (cAMP)-mediated (isoproterenol, forskolin) and cyclic guanosine monophosphate (cGMP)-mediated (sodium nitroprusside, SNP) vasodilation. Adenosine triphosphate (ATP), cAMP, and cGMP levels were quantified, and MitoQ (100 nM) co-treatment was tested for rescue effects. PFOS-exposed CPAs exhibited enhanced maximal contraction to KCl (9.73 ± 0.96 vs. 5.60 ± 0.41 mN) and ET-1 (9.84 ± 1.05 vs. 5.77 ± 0.49 mN). cAMP-dependent relaxation was impaired (isoproterenol: 31.16 ± 4.55% vs. 65.27 ± 6.08%; forskolin: 65.59 ± 2.72% vs. 87.55 ± 1.89%), while SNP-induced cGMP-mediated relaxation remained unaffected. PFOS reduced ATP by 58% (30.43 ± 2.89 vs. 73.71 ± 9.15 μmol/mg) and cAMP by 57% (46.15 ± 9.54 vs. 109.1 ± 8.88 nmol/mg) but did not affect cGMP levels. MitoQ restored ATP/cAMP levels and normalized vascular function, reversing PFOS-induced hypercontractility and cAMP pathway suppression. These findings demonstrate that PFOS directly impairs placental vascular homeostasis via mitochondrial dysfunction and cAMP signaling disruption, implicating it as a mediator of gestational hypertension. Mitochondrial-targeted interventions like MitoQ may mitigate PFOS-associated vascular dysfunction, highlighting therapeutic avenues for high-exposure pregnancies.