Arterial Smooth Muscle Proliferative Responses to ET‐1 are Subject to Hypoxic Pre‐conditioning in Term Fetal Lamb Arteries

This study explores the hypothesis that the vascular proliferative response to ET‐1 is subject to hypoxic pre‐conditioning in term fetal arteries. To test this idea, pregnant ewes were maintained at sea level or at an altitude of 3,820 m for the final 110 days of gestation. Endothelium‐denuded carotid arteries harvested from full‐term fetuses were cultured in serum‐starved media with 3, 10 and 30 nM of ET‐1 in normoxic (21% O2) and hypoxic (12% O2) chambers for 48 hours. Proliferative responses were quantified as changes in the colocalization of Non‐Muscle (NM) and Smooth Muscle (SM) Myosin Heavy Chain with smooth muscle alpha‐actin (SMaA). In normoxic fetal arteries cultured under normoxic conditions (FN‐N), ET‐1 produced a modest concentration‐dependent increase in NM‐SMaA colocalization and this effect was depressed 65% in arteries cultured under hypoxic conditions (FN‐H). In hypoxic fetal arteries cultured under normoxic conditions (FH‐N), responses to normoxic culture were not different than observed in the FN‐N group. In hypoxic fetal arteries cultured under hypoxic conditions (FH‐H), however, responses to ET‐1 were attenuated only 22%. Corresponding numbers for SM‐SMaA colocalization reflected a 46% depression in FN arteries, but 25% depression in FH arteries. Together, these results demonstrate that hypoxic acclimatization enhances the ability of smooth muscle to regulate contractile protein organization in response to ET‐1‐induced proliferation, suggesting that hypoxic preconditioning involves intracellular changes in fetal arterial smooth muscle. This work was supported by National Institutes of Health Grants HL‐54120, HD‐31266, HL‐64867, and NS‐076945 and the Loma Linda University School of Medicine.